Age-related alterations in the human blood system occur in B cells, T cells, cells of the innate system, as well as hematopoietic stem and progenitor cells (HSPCs). Interestingly, age-related, reduced genetic diversity can be identified at the stem cell level and also independently in B cells and T cells. This reduced diversity is most probably related to somatic mutations or to changes in the microenvironmental niche. Either process can select for specific clones or cause repeated evolutionary bottlenecks. This review discusses the age-related clonal expansions in the human HSPC pool, which was termed in the past age-related clonal hematopoiesis (ARCH). ARCH is defined as the gradual, clonal expansion of HSPCs carrying specific, disruptive, and recurrent genetic variants, in individuals without clear diagnosis of hematological malignancies. ARCH is associated not just with chronological aging but also with several other, age-related pathological conditions, including inflammation, vascular diseases, cancer mortality, and high risk for hematological malignancies. Although it remains unclear whether ARCH is a marker of aging or plays an active role in these various pathophysiologies, it is suggested here that treating or even preventing ARCH may prove to be beneficial for human health. This review also describes a decision tree for the diagnosis and follow-up for ARCH in a research setting.