I play the game once unmodded, then I start adding mods. I'll make a hard save at higher levels then I'll start testing mods. Most mods I'll delete because while they may be interesting once, they don't add any long term value to the game. Right now I'm running a few big mods and a dozen or so that tweak or fix things in the game. I'm running AWOP, it adds large areas to the game that actually make sense, a few companion mods that fix them and allow multi-companion play. some texture mods that make things look better, the comunity bug fix mod and a few other small mods.