Organ and tissue transplants provide a means to correct disease but are limited, mostly owing to the lack of available donor tissue. Tissue matching and speed of procurement are important parameters that must be met for a successful graft, however the lack of available donors leads to expanding waiting lists and suboptimal human leukocyte antigen-matching, often leading to reduced transplant success. The discovery of embryonic stem cells and tissue-specific stem cells has provided hope for many patients. Stem cellbased therapy has provided possible new sources of human leukocyte antigen-matched tissue but, before routine clinical application of stem cells becomes a reality, many obstacles must first be overcome. Focusing on umbilical cord blood cells, we discuss some of the challenges that stem cell therapy faces, including obtaining clinically relevant numbers of stem cells and the ability of stem cells to provide for permanent engraftment of multiple tissue types. We discuss possible solutions to these problems, such as in vitro stem cell expansion and the differentiation potential of tissue-specific stem cells.