Ultra-deep next-generation DNA sequencing of genes commonly mutated in patients with chronic lymphocytic leukaemia (CLL) has been used to investigate the clonal and subclonal dynamics of the disease. Subclonal mutations were found to be common, with or without clonal mutations. Importantly, clonal SF3B1 mutations, and clonal or subclonal mutations in ATM and NOTCH1 predicted shorter time to first treatment, independent of IGHV mutational status. Moreover, clonal and subclonal mutations in TP53, and clonal mutations in NOTCH1 were associated with shorter overall survival. Clonal evolution occurred over time, particularly after treatment, but was also observed in untreated patients. These results suggest that longitudinal evaluation of the clonal architecture of CLL could guide patient management.