Well, I started reading because of a link I got...somewhere...of webcomics with gay and lesbian protagonists. I kept reading because it's one of the few webcomics out there that's really well done, and because I found a lot in Fiona to identify with.
And then the major twist came, and I was astonished.
It reminded me of a dream I had a few years back that spanned (in the dream) over a decade. Fiona's reaction was very similar to mine when I first woke up and realized that all the people I had met, the woman I fell in love with and married, and all the things I had done never existed...it was depressing. Obviously, I got over it, but it was a powerful feeling at the time. From that point on, though, I was hooked. I know a lot of people liked the first part better, but for me the story really started getting interesting at the twist.
Now we have something more interesting than just the story of one girl's first lesbian love. I have nothing against that kind of story, it's just been done before and generally relegates the main character to a passive role as she reacts to her new feelings for another girl. In YU+ME Fiona falls into a more active role trying to save her girlfriend. And of course the setting is crazy and whimsical and fun, too. All this makes for a must-read story as far as I'm concerned.