An inconvenient hurdle in the practice of nanomedicine is the protein corona, a spontaneous collection of biomolecular species by nanoparticles in living systems. The protein corona is dynamic in composition and may entail improved water suspendability and compromised delivery and targeting to the nanoparticles. How much of this nonspecific protein ensemble is determined by the chemistry of the nanoparticle core and its surface functionalization, and how much of this entity is dictated by the biological environments that vary spatiotemporally in vivo? How do we "live with" and exploit the protein corona without significantly sacrificing the efficacy of nanomedicines in diagnosing and curing human diseases? This article discusses the chemical and biophysical signatures of the protein corona and ponders challenges ahead for the field of nanomedicine.