Regenerative medicines offer the potential for treatment and possibly cure of debilitating diseases including heart disease, diabetes, Parkinson’s disease and liver failure. Approaches using stem cells from various sources are in pre clinical and clinical testing. The goal of these studies is to deliver cellular products capable of replacing damaged tissue and/or cells. However, the balance between cellular proliferation and differentiation is a carefully controlled process involving a range of growth factors and cytokines produced in large part by tissue stromal cells. These stromal cells make up the tissue microenvironment and appear to be essential for normal homeostasis. We hypothesize that tissue damage in many instances involves damage to the microenvironment resulting in a lack of signals through growth factor networks necessary to maintain survival and proliferation of tissue specific stem cells and progenitor cells. Therefore, optimal repair of disease tissue must account for the damage to the stromal environment. We propose that optimal cellular therapies for regenerative medicine will require combination cellular products consisting of a stromal cell population to reconstitute the microenvironment and to support the survival, proliferation and differentiation of the tissue specific stem cells or progenitor cells.