Transforming growth factor‐β (TGF‐β) superfamily members are multifunctional cell‐cell signaling proteins that play pivotal roles in tissue homeostasis and development of multicellular animals. They mediate their pleiotropic effects from membrane to nucleus through distinct combinations of type I and type II serine/threonine kinase receptors and their downstream effectors, known as Smad proteins. Certain Smads, termed receptor‐regulated Smads, become phosphorylated by activated type I receptors and form heteromeric complexes with a common‐partner Smad4, which translocates into the nucleus to control gene transcription. In addition to these signal transducing Smads, inhibitory Smads have been identified that inhibit the activation of receptor‐regulated Smads. In contrast to the still growing TGF‐β superfamily (with ~30 members in mammals), relatively few type I and type II receptors as well as Smads have been identified. We will focus on recent insights into the molecular mechanisms by which signaling specificity between different TGF‐β superfamily members is achieved and regulated, and how a single family member can elicit a broad scala of biological responses.—Piek, E., Heldin, C.‐H., ten Dijke, P. Specificity, diversity, and regulation in TGF‐β superfamily signaling. FASEB J. 13, 2105–2124 (1999)