Nanoparticle delivery systems have significant potential to facilitate the delivery of novel therapeutics, such as proteins, DNA or small molecules. However, there are multiple biological barriers that need to be overcome to deliver the cargo in an active form. These challenges include evading clearance by the reticuloendothelial system, minimising adverse immune responses, targeting specific cells and tissues, and trafficking into the right compartment of the cell. In this account, we will discuss how nanoparticle structure can be tuned to optimise biological interactions and thus improve the ability of nanoparticles to overcome these barriers. The focus of this article will be on controlling cell targeting and trafficking within a cell, e.g. endosomal escape.