Population stratification, secondary effects of illness or treatment, biological heterogeneity of a clinical syndrome, or complex biology underlying a syndrome (where only one component is measured) are conditions which may obscure the association of a genetic risk factor with a clinical syndrome. We consider several investigative strategies under each of these conditions. Only segregation‐based paradigms are robust to genetic heterogeneity and population stratification. But secondary effects on the risk factor produced by illness or treatment require other strategies for their detection.