Host-related and environmental factors for tuberculosis have usually been investigated separately using different study designs. Joint investigation of the genetic, immunologic, and environmental factors at play in susceptibility to tuberculosis represents an innovative goal for obtaining a better understanding of the pathogenesis of the disease. In this paper, the authors describe methods being used to investigate these points in a West African study combining several designs. Patients with newly diagnosed smear-positive cases of tuberculosis are recruited. The effect of host-related factors is assessed by comparing each case with a healthy control from the case's household. The role of environmental factors is estimated by comparing cases with randomly selected community controls. The frequencies of candidate gene variants are compared between cases and community controls, and results are validated through family-based association studies. Members of the households of cases and community controls are being followed prospectively to determine the incidence of "secondary" tuberculosis and to evaluate the influence of geographic and genetic proximity to the index case. This type of design raises important methodological issues that may be useful to consider in studies investigating the natural history of infectious diseases and in attempts to disentangle the effects of environmental and genetic factors in response to infection.