Longitudinal acquisition of mutations may have an impact on disease course and therapeutic strategies. Recent genomic findings in CNL and aCML have indicated that mutations may arise in at least 3 different categories of genes: epigenetic modifiers, components of the spliceosome, and growth factor signaling pathways. It is likely that these mutations are acquired through a process of age-related clonal hematopoiesis (Hem) in which 1 of these mutational events initiates (A) a dysplastic or (B) a proliferative anomaly with subsequent acquisition of the other gene categories resulting in evolution to overt disease. The identity of the gene that initiates this process may have important implications for the manner in which the disease proceeds down distinct diagnostic trajectories as well as the possibility for success of targeted therapies such as tyrosine kinase inhibitors (TKIs) as well as emerging agents that target epigenetic or splicing processes.