Because of polycationic auxiliary agents such as chitosan, polyethyleneimine and cell-penetrating peptides as well as cationic lipids assembling to polycationic systems, drug carriers can tightly interact with cell membranes exhibiting a high-density anionic charge. Because of these interactions, the cell membrane is depolarized and becomes vulnerable to various uptake mechanisms. On their way to the target site, however, the polycationic character of all these drug carriers is eliminated by polyanionic macromolecules such as mucus glycoproteins, serum proteins, proteoglycans of the extracellular matrix (ECM) and polyanionic surface substructures of non-target cells such as red blood cells. Strategies to overcome this polycation dilemma are focusing on a pH-, redox- or enzyme-triggered charge conversion at the target site. The pH-triggered systems are making use of a slightly acidic environment at the target site such as in case of solid tumors, inflammatory tissue, and ischemic tissue. Due to a pH shift from 7.2 to slightly acidic mainly amino substructures of polymeric excipients are protonated or shielding groups such as 2,3 dimethylmaleic acid are cleaved-off unleashing the underlying cationic character. Redox-triggered systems are utilizing disulfide linkages to bulky side chains such as PEGs masking the polycationic character. Under mild reducing conditions such as in the tumor microenvironment, these disulfide bonds are cleaved. Enzyme-triggered systems are targeting enzymes such as alkaline phosphatase, matrix metalloproteinases or hyaluronidase in order to eliminate anionic moieties via enzymatic cleavage resulting in a charge conversion from negative to positive. Within this review, an overview of the pros and cons of these systems is provided.