Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes. Display omitted ► Whole-exome analysis of clonal heterogeneity in 149 chronic lymphocytic leukemias ► Earlier and later mutations in the temporal evolution of CLL are identified ► Clonal evolution is commonly seen with treatment, typically in a branched pattern ► A subclonal driver in a pretreatment sample is associated with adverse outcome The intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases was evaluated by whole-exome sequencing. The evolutionary patterns of distinct clones enabled a temporal ordering of mutations in CLL, revealed the association of clonal evolution with chemotherapy, and linked the presence of subclonal driver mutations with adverse clinical outcomes.