It is highly desirable to design and develop multifunctional nanoparticles for improving specificity, tumor accumulation and therapeutic efficacy. A strategy of combining active targeting with tumor microenvironmental response in one polymeric drug delivery system was developed via assembling a c(RGDfK)-linked copolymer and a pH sensitive polymer–epirubicin conjugate in aqueous solution. These hybrid micelles with a diameter of less than 100 nm showed pH sensitive drug release behaviours in vitro, which could be used for assisting tumor targeting and drug delivery. Confocal laser scanning microscopy and flow cytometry results indicated that they can enhance the endocytosis by B16F10 cells. Moreover, the hybrid micelles displayed a synergistic effect and led to increased cytotoxicity in vitro and enhanced antitumor efficacy in vivo.