The Fantastic Four were Marvel's First Family of Heroes, and they have gone on countless adventures and faced incredible threats since their first appearance in 1961. They've saved the world and the universe dozens, if not hundreds, of times, and they've traveled to worlds and dimensions undreamed of.
However, not every battle is a victory, and not every adventure is a happy one. Even the great Fantastic Four have tasted the bitterness of defeat. Sometimes, all it takes is a single opposing foe to bring even Mister Fantastic, Invisible Woman, Human Torch, and the Thing to heel.
10 Mephisto
Mephisto was able to subdue the Fantastic Four when he first captured the team and put Invisible Woman under his spell and reduced Mister Fantastic into a brainless fool. However, the team was able to signal for help from X-Factor, but, even then, the heroes were helpless to stop Mephisto. In the end, Jean Grey had to sell her soul to the devil to get the Fantastic Four and X-Factor free of Mephisto.
9 El Diablo
El Diablo, a powerful alchemist from the 9th Century, was accidentally freed by the Fantastic Four on a trip to Transylvania. The villain convinced the Thing that he could turn him back to normal with his alchemical prowess. The Thing believed Diablo, and he turned on his teammates. It seemed that Diablo's victory was assured until the Thing discovered that Diablo's alchemy was only temporary in its effect. In the end, the FF returned and the Thing helped them bring El Diablo down.
8 Terrax The Tamer
Terrax the Tamer became the Herald of Galactus some time after Silver Surfer's departure from the role. Terrax had the ability to manipulate stone and rock on a grand scale, and he was gifted with a cosmic axe to help him in his duties. Terrax forced the FF to surrender on one occasion by lifting the entirety of Manhattan thousands of feet into the air, threatening to drop it if the FF didn't capitulate.
In the end, the FF managed to win the day after Galactus removed Terrax's powers. He would later regain them thanks to Doctor Doom, and he beat the Fantastic Four once again through sheer power. However, his resentment of being under Doom's thrall ended up giving the FF an opening to turn to tide.
7 Thanos
Like many Marvel heroes, the FF have fallen victim to the sheer power of Thanos. However, it wasn't really a fair fight. When Thanos obtained the Infinity Gauntlet, he wiped out half of all life as an offering to his beloved Lady Death. The entirety of the Fantastic Four were among the heroes of Earth that were instantly slain by Thanos and only returned after a coalition of Earth's heroes, the Silver Surfer, Adam Warlock, and others were able to undo Thanos' atrocities.
6 Kang The Conqueror
Kang the Conqueror has clashed with the Fantastic Four several times over the years as well, and he managed to outwit them once while their powers were fluctuating during the Inferno event. Kang wanted revenge on the Avenger Mantis for spurning him. She and the FF tried to beat back Kang, but he was able to win the day and make off with Mantis. The FF later pursued him, but, by the time they caught up with Kang, someone else had kidnapped Mantis.
5 Silver Surfer
On the Silver Surfer's first journey to Earth, he faced the Fantastic Four. The Surfer's role was to prepare the Earth for the coming of Galactus, and he beat back the Fantastic Four. He would have followed through with the destruction of our world were it not for Alicia Masters. She managed to reach the Surfer's conscience and convinced him to turn on Galactus. In the end, Reed was able to use a weapon called the Ultimate Nullifier to repel Galactus, but the World-Devourer trapped the Surfer on our world as he left.
4 Super-Skrull
Kl'rt, the Super-Skrull, was granted the powers of the Fantastic Four and sent to Earth to take them out so the Skrull Empire could invade the planet. His version of the FF's powers were intensified to be stronger than the originals, and the Super-Skrull was easily able to overpower the team. He would have killed them and called for the invasion if Mister Fantastic hadn't built a device that jammed Kl'rt's powers by cutting them off from their source on the Skrull homeworld.
3 Annihilus
Annihilus first encountered the Fantastic Four when Sue Storm was about to give birth to her and Reed's first child, Franklin. However, the cosmic radiation that gave the Fantastic Four their powers threatened both Sue and the child's health. Reed knew that a mysterious substance called Element X could save Sue and the baby, so Reed, Ben, and Johnny ventured into the Negative Zone to get it. Annihilus' Cosmic Control Rod is made of Element X, but he refused to part with it. He was able to capture the three members of the FF, but they did escape with the Control Rod. Annihilus and his forces chased the Fantastic Four all over the Negative Zone, and the three were barely able to escape back into our world in time to help Sue.
This wouldn't be the only time the FF take on Annihilus, and the villain famously drew blood when he killed Johnny Storm during an attempted invasion of Earth.
2 The Overseer
The Overseer handed the Fantastic Four their first defeat. When Reed Richards, Sue Storm, Ben Grimm, and Johnny Storm boarded the Marvel-1 rocket, the Overseer, leader of a faraway world called Spyre believed that the four of them would arrive on their world and wreak havoc. He used a device that blasted cosmic rays at the Marvel-1, knocking it out of the sky and gifting the Fantastic Four with their incredible abilities. Their mission was a failure, and Ben's resentment of his own rocky visage would cause problems for him and his team for years to come. The FF would later make it to Spyre, but their visit was anything but pleasant or simple.
1 Doctor Doom
Of course, the Fantastic Four's greatest enemy, Victor Von Doom, has beaten the team several times over the years. He once stole the Silver Surfer's powers and beat them, he used the powers of the Beyonder to subdue three of the FF as well as several other heroes, and he made the FF his prisoners and pawns when he once again got the power of the Beyonder and created his own Battleworld. Most recently, Doom arrested the FF for unlawfully entering Latveria after they tried to help him ward off Galactus. He put them in brutal holding cells, and they were only able to escape through a plan that involved Invisible Woman making Doom's armor invisible, embarrassing Doom by exposing his scarred visage--Doom's greatest shame--to the world on a live broadcast. The FF escaped in the chaos that followed.