The AcB/BcA gene discovery platform consists of a series of 36 recombinant congenic strains (RCS) produced from the second backcross generation of the progenitor mouse strains A/J and C57BL/6J. Each individual inbred RCS carries 12.5% of the donor genome in 87.5% of the background genome. As the two parental strains are known to vary in the expression of resistance and susceptibility to a considerable number of mouse models of human diseases, the AcB/BcA RCS platform represents a valuable and versatile genetic tool to study many different phenotypes. RCS can be used to follow the segregation of single gene effects in individual strains, or to look at association/dissociation of mechanistic aspects of complex phenotypes. In addition, one can select strains with fixed alleles at known loci to look for novel gene effects, or use strains with overlapping congenic segments to delineate minimal QTL, intervals. The AcB/BcA RCS platform was used by our group and others to study a series of complex phenotypes including nociception, malaria susceptibility and lipid metabolism. Linkage mapping in secondary crosses and gene expression analysis in targeted organs allowed the identification of chromosomal regions, genes, and biological pathways which might unravel novel targets for preventive and therapeutic interventions.