Various mechanisms act in a coordinated manner to maintain proteostasis in different cellular organelles. Nevertheless, with aging, certain proteins escape proteostasis surveillance, misfold, and aggregate. This process can lead to neurodegeneration. Despite the cellular nature of proteostasis, it is regulated by intertissue communication. How these intertissue signaling mechanisms coordinate proteostasis across the organism is largely obscure. Recent studies unveiled that the transforming growth factor (TGF)-β signaling cascade is an organismal proteostasis regulator. Here, we focus on the known roles of the TGF-β pathway as a coordinator of proteostasis and describe the messengers and biological activities that are controlled by this pathway. We also discuss open questions and highlight the potential clinical relevance of these discoveries.