Nanomedicine is an interdisciplinary field of research, comprising science, engineering, and medicine. Many are the clinical applications of nanomedicine, such as molecular imaging, medical diagnostics, targeted therapy, and image-guided surgery. Despite major advances during the past 20 years, many efforts must be done to understand the complex behavior of nanoparticles (NPs) under physiological conditions, the kinetic and thermodynamic principles, involved in the rational design of NP. Once administrated in physiological environment, NPs interact with biomolecules and they are surrounded by protein corona (PC) or biocorona. PC can trigger an immune response, affecting NPs toxicity and targeting capacity. This review aims to provide a detailed description of biocorona and of parameters that are able to control PC formation and composition. Indeed, the review provides an overview about the role of PC in the modulation of both cytotoxicity and immune response as well as in the control of targeting capacity.