The field of nanomedicine has rapidly grown in the past decades. Although a few nanomedicines are available in the market for clinical use, it is still challenging to develop nanomedicine targeting tissues beyond the liver. It has been recognized that even though the nanoparticles are modified with targeting ligands, the formation of a protein corona on the surface of nanoparticles in the biological fluids results in limited progress in nanoparticle-based drug delivery to specific cells or tissues. In this Perspective, we will discuss the role of surface properties in determining the formation of the protein corona and summarize the recent progress in engineering the nano/bio interface for protein-corona-mediated cell- and organ-selective drug delivery. Moreover, current challenges in the field and insights into designing new strategies for targeting drug delivery with a better understanding of the protein corona will be discussed.