Plasma protein binding with nanoparticles (NPs) occurs immediately upon their introduction into a physiological environment and is affected by the characteristics of NPs, including their composition, size, shape and surface properties. According to their specific functions, adsorbed proteins can be divided into opsonins and dysopsonins. Opsonins often induce the rapid blood clearance of NPs, while dysopsonins benefit prolonged blood circulation. This review discusses the influential factors that are involved in the interaction between NPs and plasma proteins. The influence of this interaction on distribution of NPs was reviewed followed by the function and influence of ligand modification. Protein adsorption is a key element that influences biological responses, such as endocytosis and biodistribution, and also contributes to the characteristics of NPs and the physiological environment. By contrast, the surface modification of ligands is a common and useful method to functionalize NPs to provide an engineered targeting effect. The protein adsorption of ligand-modified NPs is even more important and requires in-depth discussion. Differences between modified and unmodified NPs lead to varying degrees of opsonization, which greatly affects targeting and may result in opposing effects. Understanding these influences is necessary to improve targeting effects and reduce defects in protein adsorption, which are crucial for drug delivery.