Infectious microbes collectively represent the strongest selective pressure operating on our species, and over hundreds of millions of years, drove the evolution of the sophisticated immune system we have today. While the general outlines of immune sensing, signaling, and effector function have been learned, we are far from achieving a comprehensive mechanistic understanding of immunity. We have limited ability to predict who will respond to a vaccine, for example, or who will develop autoimmunity. The total number of genes important for immunity and their identity remains unknown. Among those genes that are known, only rather sketchy inferences about function may be drawn in most instances. The initial goal of cataloguing all genes needed for robust immune function has advanced recently, as new technologies permit almost instantaneous identification of mutations that cause phenotype. It has thus become possible to randomly alter the genome of mice using a point mutagen, breed them to bring mutations to homozygosity, and screen them to identify impairment of immune function. As soon as data on function are developed, it is usually possible to declare the cause of any observed phenovariance. At present, it is possible to survey the effects of approximately 50,000 mutations that affect coding sense each year. Mutations affecting the antibody response, innate immune responses, and maintenance of immunological homeostasis are detected regularly, and many are “new,” affecting genes not previously known to participate in the immune response.