Chronic lymphocytic leukaemia (CLL) has several unique features that distinguish it from other cancers. Most CLL tumour cells are inert and arrested in G0/G1 of the cell cycle and there is only a small proliferative compartment; however, the progressive accumulation of malignant cells will ultimately lead to symptomatic disease. Pathogenic mechanisms have been elucidated that involve multiple external (for example, microenvironmental stimuli and antigenic drive) and internal (genetic and epigenetic) events that are crucial in the transformation, progression and evolution of CLL. Our growing understanding of CLL biology is allowing the translation of targets and biological classifiers into clinical practice.