dtgreene: I'd argue that it can ruin the game if either:
* The side event, or even just the reward for it, is permanently missable.
rjbuffchix: Interesting...because this is the kind of thing that appeals to me in a game. I guess I have roleplaying games in mind specifically. I'm not a big fan of the modern Bethesda approach where the player gets to be, simultaneously, the biggest baddest warrior, sneakiest rogue, and most knowledgeable sorcerer in all the land. It seems to me better for roleplaying games at least if there is missable content as it encourages more careful consideration and can keep playthroughs more narrowly focused (in addition to encouraging additional playthroughs to see more content by trying out different roles or choices).
I may be OK with it if it's a conscious choice that the player has to make (though being able to switch later would help).
What I am not OK with, however, is if simply progressing through the main story closes off side quests; I don't like it when the game arbitrary disallows the approach of "do main story first, then go back and do side quests that are missed". Particularly bad examples of missable treasures include one of the Blood Swords in Final Fantasy 2 (and it's the only one in GBA and later), some bard songs in Final Fantasy 5 (especially the one that raises magic power), and, in Paladin's Quest, both one of the Gigabl's (restores everyone's HP fully, 9 uses, pretty much required for the final boss) and the Heart spirit for Midia, as well as the Adult Cl.
Also, the length of the game matters; for an 8 hour game it's OK if the player has to make such irreversible choices, but in a 60 hour game it's not.