The hematopoietic system is highly dynamic and must constantly produce new blood cells every day. Mature blood cells all derive from a pool of rare long-lived hematopoietic stem cells (HSCs) that are mostly quiescent but occasionally divide and self-renew in order to maintain the stem cell pool and continuous replenishment of mature blood cells throughout life. A tight control of HSC self-renewal, commitment to differentiation, and maintenance of quiescence states is necessary for lifelong blood supply. Transforming growth factor-β (TGF-β) is a critical regulator of hematopoietic cell functions. It is a potent inhibitor of hematopoietic cell growth. However, TGFβ functions are more complex and largely context-dependent. Emerging evidence suggests a role in aging, cell identity, and cell fate decisions. Here, we will review the role of TGF-β and downstream signaling in normal HSC functions, in HSC quiescence, and beyond.