Here's #45! Click here for the master list!
Fantastic Four #45
Most creative teams, after being together for over forty issues, would begin running out of ideas. Jack Kirby and Stan Lee, though, just got better and better, as their astonishingly hot streak from issues #40-60 of the Fantastic Four demonstrates.
The FF had already encountered Medusa, as a member of the Frightful Four, and in #44, they met Gorgon (who was trying to take Medusa back to the other Inhumans), but in #45, they met the entire Royal Family of the Inhumans (by the by, what an awesome cover by Kirby!!), including the first appearances of Black Bolt, Crystal, Triton, Karnak, Maximus and Lockjaw!!
This issue would probably be on the list if it was just the first appearance of all of these Inhumans (particularly Crystal, who became a major character in the series with her relationship with Johnny Storm - even becoming a member of the Fantastic Four on at least two occasions), however, this was also the beginning of a striking multi-part storyline with the Fantastic Four aiding the Inhumans against Maximus the Mad.
So it was not only the first appearance of the Inhumans, it went right into using them in an awesome storyline.
That gets top marks in my book!
The closest competitor that I can think of is Tales of Suspense #45, which was the first appearance of both Happy Hogan AND Pepper Potts!!
And, of course, one of my personal favorite issues of all time, Justice League America #45!