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Organ transplantation has been considered to be a promising strategy to treat end-stage organ failure. However, the difficulty to procure healthy organs and tissues offers the major challenge for this treatment modality. Recently, tissue engineering (TE) and regenerative medicine emerged as an alternative approach, wherein the intrinsic healing capacity of the body is exploited to stimulate the repair/regeneration of the damaged tissues and organs. The success of TE relies on several factors such as the biomaterials employed to fabricate scaffold or preengineered tissue, type and source of cells used, and the integration of scaffolds to the host tissue. The TE approaches have thrown light to stem cells owing to their versatile regenerative potential. The promising practice is the in vitro design of preengineered tissue by seeding various preprogramed stem cells onto biomaterial scaffolds for in vivo implantation. Both adult and embryonic stem cells have been explored in combination with different biomaterial scaffolds for tissue regeneration. Still in its infancy, this approach faces certain limitations such as lack of typical stem cell biomarkers, high cost of commercialization, difficulty in clinical translations, and teratoma formation. Another strategy is to promote the homing of endogenous stem cells to injury site to initiate inherent healing response. Here, the stem cells are mobilized from their niches to circulation employing different chemokines in association with biomaterial scaffolds, as the stem cell attracting chemical cues released from the trauma site may be insufficient in severe casualties. Therefore, the exogenous supply of such signals in combination with scaffolds facilitates their local concentration to recruit stem cells to activate the tissue regeneration. Interestingly, the biomaterial-based tissue regeneration solely depends on the favorable molecular interactions at the interface between the biomaterial and host tissue. This chapter is focused on interface biology of soft tissues in regard to stem cell–based TE with a briefing on various strategies employed to improve the integration of stem cells or associated mediators onto biomaterials.