INTRODUCTION: Intravenously injected nanoparticles, like any other foreign pathogen that enters the body, encounter multiple lines of defense intended to neutralize and eliminate the invading substance. Adsorption of plasma proteins on the nanoparticle surface is the first barrier of defense, which could lead to physical changes in the formulation, such as aggregation and charge neutralization, biochemical activation of defense cascades, and trigger elimination by multiple types of phagocytic cell. AREAS COVERED: In this review, recent knowledge on the mechanisms that govern the interactions of nanoparticles (micelles, liposomes, polymeric and inorganic nanoparticles) with plasma proteins is discussed. In particular, the role of the nanoparticle surface properties and protective polymer coating in these interactions is described. The mechanisms of protein adsorption on different nanoparticles are analyzed and the implications on the clearance, toxicity and efficacy of drug delivery are discussed. The review provides readers with the biological insight into the plasma/blood interactions of nanoparticles. EXPERT OPINION: The immune recognition of nanoparticles can seriously affect the drug delivery efficacy and toxicity. There is at present not enough knowledge on the mechanisms that dictate the nanoparticle immune recognition and stability in the biological milieu. Understanding the mechanisms of recognition will become an important part of nanoparticle design.