45. Professor Layton and the Curious Village
There are a lot of puzzle games on the DS, and they probably played a decent part in its success, but few of them tried anything like Level-5 did with this series, with a story wrapped around a collection of puzzles. It worked extremely well, and is one of the standout new IPs that I've played in the last five years.
My 44th game is part of a now seemingly dormant franchise that spawned quite a few memorable quotes, one of which in particular found its way into a mainstream arena relatively recently.