The past several decades have witnessed the rapid development of nanomedicine (NM) which integrates the advancement of various interdisciplinary areas of science, engineering, and medicine. While a few clinical successes of NM greatly change the landscape of disease diagnosis and treatment, there are several areas of NM remaining to be explored. One such area is the complicated interactions between the NM and biological environment post administration, and how such interaction affects the biological performance of NM. Here, we review the recent progresses on this topic and discuss the interaction of NM with microscopic biomolecules, cells, and the macroscopic in vivo environment. The complete profiling of the bio/nanomaterials interface and interaction should have profound impact on the optimization and de novo design of new NM with better in vivo performance.