Research has advanced considerably since the first clinical trial of human mesenchymal stem cells (MSCs) in the early 1990s. During this period, our understanding of MSC biology and our ability to expand and manipulate these cells have provided hope for the repair of damaged tissues due to illness or injury. MSCs have conventionally been injected systemically or locally into target tissue; however, inconsistent cell homing and engraftment efficiencies represent a major bottleneck that has led to mixed results in clinical studies. To overcome these issues, MSCs have been pre-conditioned with biomolecules, genetically altered, or surface engineered to enhance their homing and engraftment capabilities. In parallel, a variety of cell-encapsulating materials have been designed to improve cell delivery and post-transplantation survival and function. In this review, we discuss the current strategies that have been employed on cultured MSCs to improve targeted cell delivery and retention for tissue repair. We also discuss the advances in injectable and implantable biomaterial technologies that drive the success of MSC-based therapies in regenerative medicine. Multi-faceted approaches combining cellular modification and cell-instructive material design can pave the way for efficient and robust stem cell transplantation for superior therapeutic outcomes.