Human chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. CLL has long been believed to be a single disease, but recent insights underline the biological and clinical heterogeneity of CLL. Recognition of CLL subgroups with a completely different pathophysiology and clinical course, has paved the way to better define high-risk CLL patients based on prognostic factors, to predict response to therapy, and to estimate progression-free and overall survival. Moreover, knowledge of different aspects of the (immuno) pathogenesis of CLL (genomic and epigenetic aberrations, antigenic stimulation, microenvironmental stimuli) has greatly increased. These insights are key to further develop preventive strategies and to design innovative therapeutic strategies.