Resistance to infection is largely inherited rather than acquired, and is encoded by a definable set of host genes designated the 'resistome'. Logically speaking, piecemeal disruption of the resistome gives us the best chance to define it, and the most spectacular advances in understanding innate immunity have grown from spontaneous or induced germline mutations of the resistome. Mutations induced by random germline mutagenesis have now become so numerous that we are nearly in a position to define the size of the resistome, and both random and targeted mutations give us a fairly nice sketch of its components and how they interact. Our own N-ethyl-N-nitrosourea mutagenesis effort, which recently showed that components of Toll-like receptor signaling are essential constituents of the arsenal against MCMV infections, validated the forward genetic approach as a powerful tool to define the resistome.