To break it down, there's quite a bit of content you can miss if you're not careful, and i'll explain why this happens. The story's structure actually creates several points where quests become unavailable for good narrative reasons (since some events dramatically change night city's situation).

Let me walk you through the key things to watch for. You'll want to keep an eye on that interesting little quest called bullets at the jinguji store, because the game doesn't really telegraph that you need to visit twice to see the full story. Similarly, if you pick up skippy, that talking pistol everyone loves, remember it takes 50 kills to trigger its true questline (and this is actually tied to some fascinating ai personality development).

Something that's maybe interesting - characters like panam, judy, and river have quest chains that can get locked out as you progress, because their stories are intimately tied to specific moments in night city's timeline. This is especially important with johnny's secret ending, which needs both high affinity and specific dialogue choices during that emotional conversation at the oil fields.

A good practice is to regularly check your journal for available side jobs, since many fixers will stop offering work after certain story beats. The game will eventually warn you about a point of no return, but by then, some content might already be locked (especially those hidden gems like the highwayman quest with that mysterious bike photo).

One last tip - keep a manual save before major story decisions, since some choices can permanently alter available content. This isn't just about different endings, but about preserving access to some really interesting character development arcs.