There are currently no nanoparticle formulations that optimally target diseased cells in the body. A small percentage of nanoparticles reach these cells and most accumulate in cells of the mononuclear phagocytic system. This chapter explores the interactions between nanoparticles and cells that may explain the causes for off-target accumulation of nanoparticles. A greater understanding of the nanoparticle-cellular interactions will lead to improvements in particle design for improved therapeutic outcome.