Quantum dot (QD) has been extensively investigated as a nanoprobe to replace conventional organic dyes due to its unique optical properties. However, nanotoxicity of QD greatly hampers its biomedical applications, particularly in in vivo imaging. It is critical to functionalize QD and/or composite QD with other functional materials for biocompatibility, multifunction and expanded applications. In this review, advances of QD-based nanocomposites are addressed with emphasis of their synthesis, fundamental understanding and applications in biosensor, multimodal imaging, drug delivery, diagnostics and cancer therapy. Some specific QD-based bionanosystems and future development directions are also discussed.