The transformation to a more aggressive phase in follicular lymphoma (FL) is clinically marked by rapidly enlarging lymph nodes, development of B-symptoms and often rapidly rising lactate dehydrogenase (LDH) levels and is the most frequent disease-related cause of death in patients with FL. Because of the different definitions and criteria, the incidence of transformation is reported at highly varying levels and can most probably be estimated at a 3% annual risk that remains steady during long follow-up. Several secondary genetic alterations have been associated with transformation leading to a final common result of high proliferation levels and increased metabolism. Mostly, the transformed phase has a morphology of diffuse large B-cell lymphoma, and more rarely the features reminiscent of Burkitt lymphoma or precursor B-lymphoblastic lymphoma are seen. The risk of transformation may be determined by factors that influence the relative genetic stability of the tumor genome and the relative efficiency at which the mutated clones may be eliminated. The inter-relation of the intrinsic aspects of the tumor cells, the functional composition of the non-malignant microenvironment, and constitutive patient-related properties will determine the individual risk for the transformation in patients with FL.