The recent identification of the potential for clonal replication in patients with unexplained cytopenias, resulting in myelodysplastic syndrome (MDS) or myeloid malignancies, has opened the way to identifying a new precursor entity: clonal cytopenia of undetermined significance (CCUS). CCUS has come into the spotlight in recent years with the detection of molecular abnormalities in cytogenetic studies, fluorescence in situ hybridization, and next-generation sequencing. Several clinical trials and retrospective studies are underway to examine further the associated mutation profiles, study the progression of CCUS to MDS or myeloid neoplasm, and investigate potential treatment options. In this review, we discuss CCUS-related mutations in genes such as DNMT3A, TET2, IDH1/2, ASXL1, KDM6A, PHF6, SF3B1, SRSF2, U2AF1, ZRSR2, RUNX1, BCOR, NRAS, KRAS, KIT, PTEN, CBL, TP53, and ATM. We highlight the most common mutations in CCUS, including those in DNMT3A, TET2, ASXL1, SRSF2, and SF3B1, and high-risk mutations, including those in U2AF1, ZRSR2, SRSF2, JAK2, RUNX1, and TP53. Cognizance of these mutations can guide surveillance and heighten awareness of the need to screen patients with unexplained cytopenia as a means of primary prevention in the realm of MDS and AML. Knowledge of mutation profiles, prognostic risk factors, treatment, and follow-up strategies is evolving, and prospective studies are warranted.