Clonal evolution is involved in the progression of chronic lymphocytic leukemia (CLL). In order to link evolutionary patterns to different disease courses, we performed a long-term longitudinal mutation profiling study of CLL patients. Tracking somatic mutations and their changes in allele frequency over time and assessing the underlying cancer cell fraction revealed highly distinct evolutionary patterns. Surprisingly, in long-term stable disease and in relapse after long-lasting clinical response to treatment, clonal shifts are minor. In contrast, in refractory disease major clonal shifts occur although there is little impact on leukemia cell counts. As this striking pattern in refractory cases is not linked to a strong contribution of known CLL driver genes, the evolution is mostly driven by treatment-induced selection of sub-clones, underlining the need for novel, non-genotoxic treatment regimens.