Here's #49! Click here for the master list!
Fantastic Four #49
Here's a rare one, much like Amazing Spider-Man #33, where nothing in the ways of a first appearance or the beginning of a famous run or anything like that took place in this issue, but it is still a famous enough issue that it stands out as the most notable #49 out of the bunch.
This is the SECOND appearance of both the Silver Surfer and Galactus, and it is the middle part of the classic storyline where the Fantastic Four drive off Galactus from eating Earth, and also resulting in the Silver Surfer becoming a member of the Marvel Universe proper.
This issue, which opens with one of the most iconic Fantastic Four covers ever (outside of the cover for #1, IS there a more iconic Jack Kirby Fantastic Four cover than this one? Maybe 10, perhaps 29 - Kirby even homaged 29, maybe 45 or 51? I still pick 49 as my choice).
Anyhow, this issue works as the epitome of the epic cosmic adventures Stan Lee and Jack Kirby sent the Fantastic Four on often, with wild technology and astonishing stakes (the fate of the entire planet) but at the same time, real human elements, like the Surfer's literal fall to Earth.
You could argue that this comic had it all - great story, great art, cosmic problems, earthly problems, action - it was the complete package, and it is an issue that stands out today among all the other #49s.
As for other notable ones...anyone? First Polaris in X-Men #49?