Orthopedic surgery is going through a serious paradigm shift; instead of simply replacing damaged tissues with prosthetic or allograft material, the aim is to regenerate them. This endeavor has generated the field of regenerative orthopaedics, an increasingly expanding area of research with hopes of providing new and better treatments for diseases and injuries affecting the musculoskeletal system. As part of this process, we are witnessing a substantial accumulation of new cellular and molecular insights into connective tissue function, coupled with emerging new concepts in stem cell biology and scaffolding technologies. Indeed, any successful strategy to regenerate musculoskeletal tissues can be portrayed as an intricate interplay between the three main constituents of the regenerative system: cells, environment and scaffolds. This review is not meant to be exhaustive and comprehensive, but aims to highlight concepts and key advances in the field of regenerative orthopaedics and tissue engineering, as well as to present current possibilities for clinical translation.