Raghu Kalluri’s core research interest is extracellular matrix (ECM) biology/medicine. This central interest led him to explore the role of ECM and tissue microenvironment in diseases. His early career involved the protein isolation and cloning of basement membrane proteins such as type IV collagen and laminin. Raghu Kalluri made seminal contributions in our understanding of type IV collagen’s role in the function of glomerular basement membrane, with particular emphasis on diseases such as Goodpasture Syndrome and Alport Syndrome. In the past 12 years, the focus on ECM and tissue microenvironment has led to many significant contributions in the areas of organ fibrosis, vascular biology and angiogenesis, tissue engineering and tumor microenvironment. Raghu Kalluri is a major contributor to our understanding of the role of TGF-β and BMP induced epithelial to mesenchymal transition and mesenchymal to epithelial transition in the context of organ fibrosis and cancer progression. Such findings have now led to clinical testing of BMP agonists as anti-fibrotic agents. Recently, the Kalluri laboratory discovered the contribution of endothelial to mesenchymal transition to organ fibrosis and cancer progression. An interest in vascular basement membranes led the laboratory to enter the field of angiogenesis. His laboratory discovered seven new ECM derived endogenous angiogenesis inhibitors. The anti-tumor role of tumstatin, canstatin and arresten have been well established now and more than 200 papers have been published by other laboratories validating these discoveries. Tumstatin and canstatin are currently being evaluated for clinical testing. Recently, the Kalluri laboratory has made important contributions elucidating the role of tumor microenvironment and cancer stem cells in cancer progression and metastasis.