This review article discusses the diverse mechanisms of TGF-β receptor (TGFBR) activation, highlighting the intricate processes involved in the release of active TGF-β and subsequent signaling. TGF-β signaling is crucial for various cellular functions, and its dysregulation is linked to numerous pathological conditions. The activation of TGFBRs begins with the liberation of TGF-β from its latent form, which is regulated by various mechanisms, including the action of thrombospondins, integrins, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). Different cell surface compartments and signaling pathways are involved in this process, enabling precise control of TGF-β signals. The article explores the roles of various proteins, such as thrombospondins, integrins, and MMPs, in the release of active TGF-β and the subsequent activation of TGFBRs. It also discusses the transactivation of TGFBRs by other signaling pathways, which can lead to the release of active TGF-β and the activation of TGFBR signaling. The review emphasizes the importance of understanding these mechanisms for developing therapeutic strategies targeting TGF-β signaling. Additionally, it highlights the potential of targeting TGFBR activation as a therapeutic approach, with various inhibitors and fusion proteins being evaluated for their efficacy in treating diseases such as cancer and fibrosis. The article concludes by discussing the significance of these mechanisms in the regulation of TGF-β signals and their implications for therapeutic interventions.This review article discusses the diverse mechanisms of TGF-β receptor (TGFBR) activation, highlighting the intricate processes involved in the release of active TGF-β and subsequent signaling. TGF-β signaling is crucial for various cellular functions, and its dysregulation is linked to numerous pathological conditions. The activation of TGFBRs begins with the liberation of TGF-β from its latent form, which is regulated by various mechanisms, including the action of thrombospondins, integrins, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). Different cell surface compartments and signaling pathways are involved in this process, enabling precise control of TGF-β signals. The article explores the roles of various proteins, such as thrombospondins, integrins, and MMPs, in the release of active TGF-β and the subsequent activation of TGFBRs. It also discusses the transactivation of TGFBRs by other signaling pathways, which can lead to the release of active TGF-β and the activation of TGFBR signaling. The review emphasizes the importance of understanding these mechanisms for developing therapeutic strategies targeting TGF-β signaling. Additionally, it highlights the potential of targeting TGFBR activation as a therapeutic approach, with various inhibitors and fusion proteins being evaluated for their efficacy in treating diseases such as cancer and fibrosis. The article concludes by discussing the significance of these mechanisms in the regulation of TGF-β signals and their implications for therapeutic interventions.