TileMill is good software. It's a turnkey system for designing custom slippy maps for web publication. It's very easy; in four hours I was able to create a simple map of US airports and airspace without having much background in the software or GIS concepts involved. Making a map requires a bunch of things: data, style, publication. There's been open source ways to do this for a few years but it's pretty complex tech, TileMill makes it much simpler. I put my project up on GitHub, the map is live. Natural Earth like country outlines, roads and rivers, and urban areas. I added custom data: airport locations from GeoCommons KML and airspace definitions from FAA shapefiles. Easy to add, just a bit of sweating the missing projection metadata from my sources.
Designing is where TileMill really shines, a beautiful browser-hosted GUI for making maps. You style the map in Carto, a simple CSS-like language (here's my style file). The development environment includes a live view of generated tiles and a great little editor. Really a joy to use, especially considering all the complex Mapnik stuff going on behind the scenes. TileMill is capable of more complex design than I used, like labels and interaction, but it's also deliberately simplified compared to using the underlying tools directly.
Publication is simple. You can create single PNG or PDF images like this. Or you can generate an MBTiles file, a bundle of all the pregenerated tiles for a web map. Hosting a map at web scale yourself is a bit complicated. But you can upload your tiles to the inexpensive TileStream hosting service or just copy it to the free iPad app for personal use.
I've been learning about open source geo for a year now and it's easy to get overwhelmed. TileMill is impressive in how it combines so many powerful tools into an easy to use product. Great work by Development Seed, the company behind TileMill. They're supporting a lot of interesting humanitarian projects with great mapmaking tools.