Jeph is consistent enough with his character development, not to mention his situational development, that one really has to start with #1 to get a proper feel for what's going on (for example, Sara is mentioned much later, can't recall when, but it results in Penelope getting hired), although I'll say that you can get most of it anywhere in the 200-300's, and things pick up a bit.
Not that I'm a fan of indie music (well, maybe Cat Power), but I don't see why the indie refs should bog anyone down. One of the things I like about webcomics is many of their creators don't attempt to appeal to everyone. One of the upshots of this is you can learn all sorts of things if you follow up the things you don't get immediately.
Anyway, I found it absolutely fascinating to watch the storyline unfolding (is that the right term for going through something backwards? Maybe it's de-folding, or refolding...), seeing where characters and situations came from.
Regressing.