Susceptibility to many important human diseases such as infections and inflammatory disorders is under complex genetic control. In order to facilitate the identification of candidate susceptibility genes for complex diseases, we have developed a gene-discovery platform in the mouse uniquely suited to the genetic dissection of complex traits, termed recombinant congenic strains (RCS). The platform consists of a panel of 42 RCS constructed from two progenitor strains which are well known to vary widely in the expression of a considerable number of mouse models of important human diseases. RCS with the most discontinuous disease phenotypes can therefore be targeted for gene discovery by the combination of positional cloning and the candidate gene approach, allowing a new powerful approach to map, isolate and study the action (and interaction) of the individual genes. We have undertaken a project to discover genes controlling the phenotypes of asthma and tuberculosis using the RCS. We also intend to identify the discrete mechanistic phenotypes affected by these loci. A particular emphasis will be on the regulation of T helper subset selection, an immunological pathway of pivotal importance in the susceptibility or resistance to pathological inflammation.