Genetic tools (especially classical tools) have enlightened our understanding of biology as no other approach could. Mendel, Morgan, Bridges, and their heirs began with phenotypic traits and ended with genes. At first, the chemical identity of genes was not known, and even after years of methodologic refinement, more years of effort were needed to find the gene and the mutational difference that caused a particular phenotype. Chemistry has now outraced phenotypic analysis; all the genes are suddenly known, but most of their functions are not. The greatest challenge confronting all fields in biology is to establish correspondence between genes and discrete biologic functions. Sepsis is a devastating problem that has eluded a solution, despite the introduction of highly effective antimicrobial agents. Sepsis is an orchestrated process, understood in broad outline, but not in all details. Which genes are involved in the pathogenesis of sepsis? As in the golden age of genetics, the answer requires the solution of phenotypic puzzles, which, in turn, requires the creation of phenotypes.