Polymeric nanoparticles have demonstrated enormous potential as cellular drug delivery vehicles. Nanoparticles improve drug's stability as well as its availability and retention at the target intracellular site of action. Therapeutic efficacy of nanoparticles can be further enhanced by conjugating specific ligands to nanoparticle surface. Ligand conjugation can also be used to favorably modify the intracellular disposition of nanoparticles. A number of ligands are available for this purpose; use of a specific ligand depends on the target cell, the material used for nanoparticle formulation, and the chemistry available for ligand-nanoparticle conjugation. Cellular drug delivery using nanoparticles is also affected by clearance through the reticuloendothelial system. In this paper, we review the recent progress on our understanding of physicochemical factors that affect the cellular uptake of nanoparticles and the different cellular processes that could be exploited to enhance nanoparticle uptake into cells.