Protein coronas can introduce new unexpected applications and shortcomings for the biomedical application of nanoparticles. For instance, it is now well recognized that the protein coating reduces the targeting capability of surface-engineered nanoparticles by screening the active sites of the targeting ligands. On the contrary, the unique features presented by protein coronas can be exploited in the design of the nanomaterial, rather than combat their adsorption. Therefore, in this chapter, the advantages and disadvantages of protein–nanoparticle interactions with their corresponding biological impact have been discussed. In addition, a broad overview of the available data of both in vitro and in vivo protein–nanoparticle interactions is provided. Uncontrolled protein coronation can pave the way for cytotoxicity, a reduced blood circulation half-life, and minimized targeting efficiency. However, a comprehensive understanding and design of suitable nanomaterials with varied functional proteins can allow selective protein coronation, which can help to tailor their therapeutic properties for nano-drug delivery vehicles.