Follicular lymphoma (FL) is the second most frequent type of non-Hodgkin's lymphoma in adults. The disease is characterized by an indolent course with frequent relapses. Ultimately, resistance to chemotherapy or transformation to a more aggressive phase of the disease in the form of diffuse large B-cell lymphoma develops, and patients die as a result of their disease. Median survival is 8 to 10 years. The range is very wide, however, with patients surviving for more than 15 years and 10% to 15% of the patients who run a rapidly fatal course and die within 3 years after diagnosis. The translocation t(14;18) is the basic molecular defect in FL and results in protection from apoptosis by aberrant overexpression of bcl-2 protein. Accumulation of genomic alterations and clonal selection account for subsequent progression and transformation. Recently, the role of the immunologic microenvironment of FL in determining clinical behavior and prognosis has been substantiated. Combined genetic and immunologic data may now support a model for the development of FL as a disease of functional B cells in which specific molecular alterations infer intrinsic growth properties of the tumor cells as well as dictate a specific functional cross talk with the immunologic regulatory network resulting in extrinsic growth support. These insights may lead to improvement of risk stratification, but most importantly will provide tools for developing new targets and strategies for treatment.