Kana: Little Sister is a mindfuck. Not like The Matrix or A Scanner Darkly, but in a much more down-to-Earth way. It's a Japanese visual novel (think choose-your-own-adventure book with illustrations and sound) about a young man called Taka, and his relationship with his sickly little sister, Kana.
Kana spends almost all of her life in hospital due to renal insufficiency - her kidneys don't function properly, causing all sorts of problems and forcing her onto a dialysis machine every week.
Taka bullies his little sister but when he is ten-years-old, an event forces him to re-evaluate their relationship and become a better brother. You then join Taka for ten years, visiting Kana in hospital and showing her the world outside.
Kana is two years younger than Taka. As they grow up Taka begins to confuse his co-dependency with his sister, and his affection for her with sexual urges. It's definitely uncomfortable, but developer D.O. does a very good job of making it believable - having it gradually build, and the main character resist it with self-disgust. At the very end you can have sex with Kana; the way this is justified, although credible, seems like an afterthought.
Everyone writing about this game categorizes it as an eroge ( erotic/porn game). The two sex scenes I clicked through seemed utterly disposable though. The developers must have agreed with me, as they were once remaking it for the original Xbox - and there's no way Microsoft (or any other major console manufacturer) would allow pornography on their console. Perhaps it's unfair to criticize this for it's pornographic merit, but I didn't find it at all titillating.
The two main female characters are very exploitative; Kana couldn't be more pitiful if she was a three-legged puppy and Yumi, your traditional girlfriend character, seems to live only for you.
After she hurts him in grade-school, Taka hates Yumi until they meet again at college. All this time she has been unable to love anyone but him. There's nothing particularly appealing about Taka, so the idea that this ideal girl has been waiting for him falls flat. She has little more dimension than any female character in Western pornography - a vacuous beauty who only finds pleasure in the player's avatar.
I can pick other nits: spelling mistakes in the English translation, a cheesy soundtrack, an implication that child-Taka is molested which is never resolved. I was on the verge of tears several times though, shared Taka's disgust with himself at others, and was left temporarily dumb-struck even by the non-canonical, unhappy ending I reached. (There are 6 endings, only one of them happy. One of the sad endings is canonical.)
Apparently fans point to Kana: Little Sister as the best example of a visual novel. It's the only one I've played, but if you don't mind your brain being assaulted by incestuous themes and an extremely depressing story, it's the most emotionally exhaustive and effective drama I've seen in a video game.