Genetic predisposition to cancer is influenced by allelic variation in tumor susceptibility genes (TSGs) as present in the germline. We previously demonstrated in the mouse that TSGs frequently participate in genetic interactions, indicating that they represent molecular networks. Inflammation may constitute one of the molecular networks underlying susceptibility to cancer by influencing the tumor microenvironment. Because macrophages play a key role in inflammation and are often associated with tumors, we argue that a subset of TSGs can be identified by examining the genetics of macrophage characteristics. A panel of inflammation-related assays was established to phenotype mouse bone marrow-derived macrophages, which included stimulation with lipopolysaccharides followed by measurement of secretion of tumor necrosis factor alpha and the p40 chain of interleukin-12 and of expression of inducible nitric oxide synthase and cyclooxygenase-2. This panel of assays was used for linkage analysis and applied to bone marrow-derived macrophages derived from individual mice of segregating crosses between inbred strain O20 and the highly related strains NTX-10 and NTX-20, which differed from O20 in only 10% of their genome, to reduce genetic complexity. Three macrophage-associated risk inflammatory factors were mapped-Marif1, Marif2, and Marif3-that each affected several inflammation-related assays, confirming that they function within molecular networks. Moreover, Marif1 and Marif2 were localized in regions with established linkage for both quantitative and qualitative aspects of lung cancer susceptibility. These studies provide a novel approach to investigate the genetics of microenvironmental influence on predisposition to tumorigenesis, thereby contributing to development of new strategies that aim to prevent or treat cancer.