The transforming growth factor (TGF)-beta superfamily of growth factors, including the TGF-betas, activins, and bone morphogenetic proteins (BMPs), provide cells with a broad spectrum of regulatory signals through the intracellular Smad pathway. Since loss-of-function studies of a majority of the TGF-beta superfamily members result in embryonic lethality, much of our current knowledge of the TGF-beta superfamily's role in hematopoiesis is generated from studies performed in vitro, or in very early stages of embryonic development. TGF-beta is well documented as a potent inhibitor of hematopoietic stem cell (HSC) proliferation in vitro, while its role in vivo is largely unknown. BMP signaling is crucial for the initiation of hematopoiesis in the developing embryo, although its role in adult hematopoiesis remains elusive. More recently we and others have used conditional knockout models to unravel the role of several components of TGF-beta family signaling in adult hematopoiesis. Here we review the currently known functions for the major factors of this signaling family in embryonic and adult hematopoietic regulation and discuss the context dependency and complexity that permeate this regulation.