Chronic lymphocytic leukaemia (CLL), the most frequent type of leukaemia in adults, is a lymphoproliferative disorder that is characterized by the expansion of monoclonal, mature CD5+CD23+ B cells in the peripheral blood, secondary lymphoid tissues and bone marrow. CLL is an incurable disease with a heterogeneous clinical course, for which the treatment decision still relies on conventional parameters (such as clinical stage and lymphocyte doubling time). During the past 5 years, relevant advances have been made in understanding CLL biology. Indeed, substantial progress has been made in the identification of the putative cell of origin of CLL, and comprehensive studies have dissected the genomic, epigenomic and transcriptomic landscape of CLL. Advances in clinical management include improvements in our understanding of the prognostic value of different genetic lesions, particularly those associated with chemoresistance and progression to highly aggressive forms of CLL, and the advent of new therapies targeting crucial biological pathways. In this Review, we discuss new insights into the genetic lesions involved in the pathogenesis of CLL and how these genetic insights influence clinical management and the development of new therapeutic strategies for this disease.