The genetics of natural resistance to salmonellae were studied in F1 hybrid and backcross mice. Overall resistance to Salmonella typhimurium C5 is complex, but one parameter, the early net growth rate of the organism in vivo, is controlled by a single autosomal gene or cluster of genes. 'Slow' net growth rate is necessary but insufficient, for resistance to S. typhimurium C5. Resistance requires the participation of other mechanisms, detectable by the end of the first week, which presumably involve an immune response. F1 hybrids bred from parents of low, intermediate and high natural resistance showed either high or low resistance. Most of the F1 hybrids were of a similar high resistance, and were bred from pairs in which at least one parent showed slow net growth rate. Hybrids of low resistance were only obtained when neither parent showed slow net growth rate. No hybrid was less resistant than the parents, many were more resistant. Backcross analysis on two hybrids challenged with S. typhimurium C5 supports the hypothesis of complex genetic control of overall resistance but with single gene control of the early net growth rate of the organism. Similar experiments were performed using a much more virulent organism, S. enteritidis 5694. All mouse strains were very susceptible (LD 50 less than ten organisms) to this strain given either i.v. or s.c. This organism produced an overwhelming infection which did not allow the cell-mediated immune response time to develop. This, however, did not interfere with the mechanism controlling early net growth rate, and genetic analysis using this organism gave similar results to those obtained with S. typhimurium C5. These results suggest that the mechanism regulating early net growth rate does not operate via the cell-mediated immune response, which develops later in the course of the infection.