The promise of nanobiomaterials for diagnostic and therapeutic biomedical applications has been widely reported throughout the scientific community, and great strides have been made in those directions. And yet, the translation of nanomaterial-based therapeutics to clinical applications remains an elusive target. Many challenges have blocked the usage of nanomaterials in biomedicine, including potential toxicity, immunogenicity, and decreased efficacy. In order to overcome some of these issues, detailed studies have been undertaken to understand fundamental interactions between nanomaterials and the biological environment. In particular, recent developments in nanoparticle synthesis, a better understanding and control over nanoparticle surface chemistry, as well as the organization of that chemistry on the nanoparticle surface, has allowed researchers to begin to understand how spatial arrangement of atomic and molecular species at an interface can affect protein adsorption, structure, and subsequent biological outcomes. This perspective strives to identify ways in which the nanomaterial interface can be controlled to affect interactions with biomolecules for beneficial biomedical applications.