Interfaces between biomaterials and living system are critical in regulating their interactions. Poor biocontact properties always limited the performance of biomaterials in biological environment. Surface engineering aims to control the interface interaction to further enhance the desired behavior of biomaterials. Upon implantation of biomaterials into the biological environment, a series of host responses are initiated. Non-specific protein adsorption on biomaterials is the essential stage of all biological reactions that associated with implants failure, device-related infections and blood-coagulation. In this review, we first focused on surface modification techniques to eliminate protein adsorption by emphasizing PEGylation of both macroscopic surface and nanoparticle system. Next, recent developments in surface engineering of biomaterials to optimize interactions between biomaterials and specific host tissue and organs are discussed. Optimizing the biocontact property of blood-contact devices can improve their hemocompatibility and maintain vascular homeostasis. Surface modifications of orthopedic and dental implants confer improved osteointegration and tribology performance. Controlling the surface chemistry and topography, and immobilizing biomolecules can aid the expansion and direct the differentiation of stem cells.