The pancreas is a complex exocrine and endocrine gland that controls many homeostatic functions. The exocrine pancreas produces and secretes digestive enzymes, whereas, the endocrine pancreas produces four distinct hormones, chief among them being the glucose regulating hormone-insulin. Diabetes, pancreatitis and pancreatic cancer are some of the main afflictions that result from pancreas dysfunction. Transforming growth factor-beta (TGF-beta) proteins are central regulators of pancreas cell function, and have key roles in pancreas development and pancreatic disease. Since expression levels and kinase activities of components of TGF-beta signaling are aberrantly altered in diseases of the pancreas, modulating the activity of TGF-beta provides a unique and rational opportunity for therapeutic intervention. Although TGF-beta still remains elusive in terms of our understanding of its multifunctional modes of action, research is moving closer to the design of approaches directed toward modulating its activities for therapeutic benefit.