Transforming growth factor βs (TGF-βs) are closely related ligands that have pleiotropic activity on most cell types of the body. They act through common heterotetrameric TGF-β type II and type I transmembrane dual specificity kinase receptor complexes, and the outcome of signaling is context-dependent. In normal tissue, they serve a role in maintaining homeostasis. In many diseased states, particularly fibrosis and cancer, TGF-β ligands are overexpressed and the outcome of signaling is diverted toward disease progression. There has therefore been a concerted effort to develop drugs that block TGF-β signaling for therapeutic benefit. This review will cover the basics of TGF-β signaling and its biological activities relevant to oncology, present a summary of pharmacological TGF-β blockade strategies, and give an update on preclinical and clinical trials for TGF-β blockade in a variety of solid tumor types.