It has been more than one century since Paul Ehrlich spoke about the idea of targeting specific molecules in the cell when he coined the 'Magic Bullet' principle. In most occasions, we seek new pharmacodynamic models for therapy, but nanoparticles provide a chance to modify the already existing pharmacokinetics of drugs to meet needed pharmacodynamic models. In the scope of 'nanoscale', every entity has different characters, and no general rules control pharmacokinetics of nanoparticulate drugs as new physical and physicochemical properties are added to equations. However, such remarkable drug models are still quite far from achieving their potential in clinical application. Among the major obstacles is that most available results in nanoparticles targeting rely upon in vitro and animal models that do not match the tumor environment characteristics in humans. This Review discusses the concept of targeting tumor cells with nanoparticles, the limitations that lead to its incomplete application in clinical practice along with some of the promising solutions to such limitations.