The Development Seed (MapBox) team developed the UTFGrid spec to provide interactivity to raster map tiles. It's pretty rockin'.
In more detail, the UTFGrids are invisible “ASCII Art” and attribute data embedded in json. They sit “behind” your map tiles (they are not rendered visually) and allows quick attribute lookups without going back to the server. This allows a high degree of real-time map interactivity in an HTML web map - something that has typically been the strong point of plugin-based maps.
UTFGrids with OpenLayers and Tilestache - Great tutorial from PerryGeo.
See How Utfgrid Works Visible Map - Visible map is a toy that lets you see all of the magic at work behind our maps and the way that we do interaction with UTFGrid. It works by spying on the workings of Wax and Modest Maps while they do the dirty work of building maps, downloading grids, and producing pretty tooltips. It’s stuff that we work hard to make invisible, but this is all of that turned inside out so that you can can see how it works.
Use TMS-based tile rollcalls to track which features are visible where, deduplicate that list client side, and request those feature GeoJSON files. An experimental feature of TileStache.