Diabetes mellitus is a metabolic disease characterized by an inability to maintain normoglycemia and is usually associated with an insufficient beta-cell mass. Islet transplantation (IT, a beta-cell replacement therapy) has exhibited promise in reversing the diabetic state, yet it remains an experimental therapy only among a small subset of patients and widespread availability remains elusive. A main reason for its limited use is the large islet dose required to produce insulin independence, often requiring tissue from multiple donor pancreata. Abundant evidence exists suggesting that acute and chronic islet loss and dysfunction occur in the post-IT period. The minimum islet dose could be reduced if the quality (potency, viability) of the islet product is improved. Since islets do not possess the cellular machinery to produce energy effectively in the absence of oxygen, strategies that improve oxygenation during the ischemic period (donor cardiac death to complete revascularization) are important to develop. Due to the many steps involved in the process (pancreas preservation, and islet isolation, purification, culture, assessment, transplant and engraftment), the quality of an islet preparation can change. Thus, it is critical to develop improved islet quality assessment tools that enable accurate and quantitative characterization of islet viability and potency, which can be performed prospectively, and which do not require much tissue for assessment or which rely on non-invasive methods. Furthermore, intrahepatic IT may not be the optimal approach, and tissue-engineered strategies for extrahepatic IT may be better. The work presented herein focuses on improving islet quality assessment, examining the oxygenation status of the intraportally transplanted islet, and developing a tissue-engineered strategy for the design and non-invasive assessment of islet graft viability - all with the hope that someday IT could be used to successfully treat many more diabetics.