Clonal hematopoiesis (CH) is common in middle-aged and elderly populations and confers a risk of hematological malignancy and also death due to cardiovascular disease. Prior therapy with cytotoxic chemotherapy or radiation increases the risk of CH, especially that associated with TP53 or PPM1D mutations. CH can complicate interpretation of cell-free or circulating tumor DNA assays, since most blood DNA is derived from hematopoietic cells. The specific determinants of clonal progression are unclear, but the gene carrying the mutation, size of the mutant clone, and presence of multiple mutations appear to increase risk of evolution to myeloid leukemia. While CH is not yet modifiable, specific mutations such as TET2 or IDH1/IDH2 confer vulnerabilities to established drugs or developmental compounds, and investigators are developing clinical trials to try to exploit these vulnerabilities.