Eukaryotic cells constantly form and internalize plasma membrane vesicles in a process known as endocytosis. Endocytosis serves a variety of housekeeping and specialized cellular functions, and it can be mediated by distinct molecular pathways. Among them, internalization via clathrin-coated pits, lipid raft/caveolae-mediated endocytosis and macropinocytosis/phagocytosis are the most extensively characterized. The major endocytic pathways are usually distinguished on the basis of their differential sensitivity to pharmacological/chemical inhibitors, although the possibility of nonspecific effects of such inhibitors is frequently overlooked. This review provides a critical evaluation of the selectivity of the most widely used pharmacological inhibitors of clathrin-mediated, lipid raft/caveolae-mediated endocytosis and macropinocytosis/phagocytosis. The mechanisms of actions of these agents are described with special emphasis on their reported side effects on the alternative internalization modes and the actin cytoskeleton. The most and the least-selective inhibitors of each major endocytic pathway are highlighted.