The onset, progression and outcome of infections are determined by performance of host defence mechanisms and expression of pathogen virulence determinants. Genetic analysis in mouse can identify host genes that play critical roles at the interface of host-pathogen interactions. Genetic effects detected as variations in susceptibility in inbred, recombinant and mutant strains of mice can be mapped as simple traits or quantitative trait loci followed by identification by positional cloning. We have used mouse models of infection with bacterial (Mycobacterium, Legionella) and parasitic pathogens (Plasmodium) to discover genes and proteins that are important for macrophage function against such infectious agents. These studies have identified Nrampl-mediated exclusion of divalent metals from the phagosomal space as a key regulator of intracellular replication of Mycobacteria. Also, intracellular sensing of Legionella by functional Birc1e/Naip5 protein is essential to prevent replication of this bacterium in macrophages. Finally, we have identified two new loci that affect blood-stage replication of Plasmodium chabaudi AS in mice, and have cloned the corresponding genes.