The Smad Ubiquitination Regulatory Factor-1, or Smurf1, is an E3 ubiquitin ligase that catalyzes mono- or polyubiquitylation of protein targets which primarily function in TGFβ signaling pathways, but also include a growing list of substrates encompassing other molecular pathways and cellular processes distinct from TGFβ pathways. Smurf1 and a close homolog, Smurf2, are E3 ubiquitin ligases that belong to a small family of proteins distinguished by the presence of a catalytic, C-terminal region that is known as the HECT domain, for Homologous to E6AP C-Terminus. This region of the Smurfs and other HECT E3s form a covalent intermediate with ubiquitin (Ub) and subsequently transfer the Ub moiety to a substrate protein whose selection and targeting are governed by either direct interaction with Smurf1, or in concert with an adaptor protein(s) that bridges Smurf1 and the substrate. Smurf1 can operate throughout the cell and has a wide variety of protein targets, reflecting the diversity of biological processes it regulates, which spans cell proliferation, cell polarity, adhesion, apoptosis, differentiation, stem cell activity, embryonic development, pattern formation, organogenesis and organism physiology. Smurf1 is expressed in a wide range of cell types in developing embryos through adults, and Smurf1 gene orthologs are found in all lineages of the animal kingdom, from sponges through chordates. Defects in Smurf1 gene structure, expression or regulation are implicated in human diseases and birth defects, and Smurf1 is being actively pursued as a therapeutic target.