Clathrin-independent endocytosis occurs in all cells and interest in this mode of cellular entry has grown. Although this form of endocytosis was first described for entry of bacterial toxins, here we focus our attention on the endogenous cell surface “cargo” proteins that enter cells by this mechanism. The cargo proteins entering by this mechanism are varied and include nutrient transporters, ion channels, cell adhesion molecules and proteins associated with the immune system. Despite the apparent lack of selection at the cell surface, we provide some examples of specific sorting of these cargo proteins after entry, leading to distinct itineraries and cellular fates. •CIE mediates the entry of PM proteins with a wide variety of functions.•CIE cargo proteins are sorted on endosomes.•Recruitment of Rab proteins to endosomes regulates CIE cargo trafficking.•CIE is fundamental for cell migration, nutrient metabolism and immune defense.