Proteins are among the significant biomolecular constituents in a biosystem. The structure of proteins and the nanomaterials, intracellular interactions, type of the cell, cell organelles, cell signaling and sensation, etc., affect the interactions between proteins and the nanomaterials. The interface formed between proteins and nanomaterials is the original site of contact and the interplay. The behavior of the interacting components reflects on the regulatory aspects, assembly of biomolecules, and various applications in the normal functioning of a biosystem. The fundamentals related to the tendency of biomolecules and nanomaterials help to retain their stable physicochemical conformations. The interactions involving proteins and nanomaterials bring changes in both. It is essential and beneficial to understand the mechanism of these interactions and their impacts on each other. This chapter deals with the nature, structure, and behavior of protein in general and nanomaterials, their stability, the significance of zeta potential, opsonins and their role, protein corona, and the factors influencing their dynamics.