Histologic transformation (HT) to an aggressive lymphoma is a well-described event in the natural history and clinical course of patients with so-called indolent lymphomas. This phenomenon has been studied most extensively in patients with follicular lymphoma and subsequent transformation to a diffuse large B-cell lymphoma, with little literature on HT in nonfollicular lymphomas. Despite a considerable body of information on the pathologic and molecular events associated with HT, its pathogenesis has remained elusive and the molecular information available has not been translated into clinical advances. It remains unclear if there is already a predisposition to HT and whether this can be detected at the time of diagnosis. The rituximab era has been characterized by a significant improvement in the prognosis of patients with B-cell lymphomas, but HT remains one of the most important challenges in the management of patients with indolent lymphoma, the difficulties starting with the diagnosis and definition of HT and ending with the appropriate management and treatment of the event. Going forward, it is crucial to incorporate HT as a major end point in clinical trials and to include patients with HT as subject of such studies if we are to see meaningful progress in the future.