The setting: a post-apocalyptic version of the US that got stuck in the 50s culturally, but advanced massively in technology - I haven't played the first two, but I just love that off-kilter setting. The SPECIAL system that defines your underlying stats (Strength etc) is familiar territory, while it's slightly more complex than the standard AD&D ability scores, I've seen (for example) the Luck attribute appear in quite a few JRPGs.
Ok, it's mostly Oblivion with guns, but with a few significant differences - the biggest being the VATS combat system. This is an optional mode where you can freeze the action and auto-aim at a specific part of a monster, as many times as your Action Points allow. It goes all slo-mo cinematic and your proximity, line of sight, skills (and Luck) take over, with you hitting like it's a turn-based combat game - then it jumps back to real-time so you can dodge any retaliation while your APs regenerate. Non-VATS is just like a normal FPS, and the main reason the PC release shades the console ones, but it would be perfectly playable using only VATS. Since I didn't play the earlier incarnations, I'm gonna continue comparing it to Oblivion.
Other good changes are fully remappable keys (there's a line at the top of the readme about how to map the mouse, perhaps clumsier than it should be, but it's there), a nice range of toys to shoot at stuff, a much-simplified crafting interface and more variety in costumery.
Bad changes would be that each weapon needs very specific ammo, the weapons break very easily and you need identically-described weapons to repair existing ones, so inventory space gets used up pretty quickly.
Another change is that all skills have to be bought at level-up, so while the enemies get tougher, you should theoretically be getting tougher yourself (rather than only leveling when you improved key class-stats) but you can no longer learn things like stealth simply by creeping around a lot.
What's not changed are instant-travel nodes on the map, the clumsy way the map, inventory and skills are on separate tabs within the same menu and you constantly need to switch between them, the same rather basic compass, characters and monsters seeming to pop out of nowhere and giving you a heart-attack, and the monster NPCs having AI like the red ghost in Pac Man.
Still it's a excellent game, the VATS system never seems to get old as you think it might and the setting is amazing.