Transforming growth factor-beta (TGF-beta) represents a large family of growth and differentiation factors that mobilize complex signaling networks to regulate cellular differentiation, proliferation, motility, adhesion, and apoptosis. TGF-beta signaling is tightly regulated by multiple complex mechanisms, and its deregulation plays a key role in the progression of many forms of cancer. Upon ligand binding, TGF-beta signals are transduced by Smad proteins, which in turn are tightly dependent on modulation by adaptor proteins such as embryonic liver fodrin, Smad anchor for receptor activation, filamin, and crkl. A further layer of regulation is imposed by ubiquitin-mediated targeting and proteasomal degradation of specific components of the TGF-beta signaling pathway. This review focuses on the ubiquitinators that regulate TGF-beta signaling and the association of these ubiquitin ligases with various forms of cancer. Delineating the role of ubiquitinators in the TGF-beta signaling pathway could yield powerful novel therapeutic targets for designing new cancer treatments.