The aim of this review was to describe the preferred charged nano-particles (CNPs) for targeted delivery in tumor cells. Zeta Potential (ZP), which represents the surface charge of NPs was highlighted in cell entrance and interactions. In this regard, various types of endocytosis pathways which are involved in NPs' uptake were first introduced. Then, significance of positively charged NPs (PCNPs) in proton sponge effect corresponding to lysosomal escape was discussed. Cells prefer to endocyte the NPs with positive charge in passive targeting and gene delivery, while in active targeting; the charge of receptors' ligand binding site determines the NPs cellular uptake. Moreover, pH-sensitive NPs represent charge reversible behavior depending on pH changes which leads to longer blood circulation residence and higher uptake at acidic microenvironment of the cancer media. Role of the CNPs in overcoming multidrug resistance (MDR) and bypassing p-glycoprotein was further investigated.