There's a reason why Spider-Man is consistently Marvel's number one comic seller by a huge margin. The character of Peter Parker is so relatable and timeless that millions of people have looked up to him as a role model and inspiration for decades. If anyone can claim the title of "The Face" of Marvel comics, it would be Spider-Man. That doesn't mean things are all rainbows and butterflies for everyone's favorite webhead, though.
Perhaps more than any other Marvel character, Spider-Man has been through the wringer. He often faces challenges that leave him broken and questioning his worldview. With all that's happened to him, it's a wonder he's still the Friendly Neighborhood Spider-Man.
Although the Marvel Zombies brand should never be taken too seriously, it would be an oversight not to mention Spider-Man's demise in Marvel Zombies Return #1. The event takes place on Earth-91126, where that world's Spider-Man is almost exactly like our own. The Sinister Six appear and Spidey goes to change into his costume.
While he's gone, the zombie version of Spider-Man appears and offs almost all of the Sinister Six. Sandman escapes, but then runs into the real, still alive Spider-Man. Sandman is so scared and angry that he goes into a rage, pouring himself into Spider-Man's mouth.
In the comic crossover story arc The Other, it really sucks to be Spider-Man. See, Spidey learns he has a radiation-based illness that is making him disoriented and weaker in fights. He talks to all of his superpowered friends (including Bruce Banner and Doctor Strange) and they all tell him the same thing: his days are numbered.
To make matters worse, the supervillain Morlun is hunting Spider-Man at the time in order to drain his life force. In The Amazing Spider-Man #526, he finally catches up with the webhead. A massive battle takes place across New York City, and Spider-Man is overpowered.
One of the most celebrated Spider-Man stories of all time is the famous (or infamous) Kraven's Last Hunt. Spanning six issues, it brought Spider-Man to a much darker place than had ever been before. The story revolves around Kraven the Hunter, a relatively unpopular villain at the time, coming to New York to prove he can beat Spider-Man.
Rather shockingly, he succeeds in everyway. He outwits and outfights Spider-Man, injects him with a powerful drug that keeps him comatose, and then buries him alive for two weeks.
The Infinity Gauntlet is a powerful artifact in the Marvel Universe that basically allows the wielder to do whatever they want with reality. In the comic Infinity Gauntlet #4, pretty much all of Earth's heroes go up against Thanos, the big bad to end all big bads.
As the Mad Titan is destroying all of the universe with his reality-altering power, our heroes try their best to stop him. In the end, Spider-Man is offed by Thanos's minion Terraxia. Fortunately he gets revived at the end of the series.