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Endocytosis, the procedure whereby the plasma membrane invaginates to form endosomes, is essential for bringing many materials into the cell and for membrane recycling. Multiple cellular processes require endocytosis, including nutrient uptake, signal transduction, and cell-pathogen interactions. The fate of cargoes internalized in early endosomes depends on their nature. Some cargoes are recycled back to the plasma membrane, while others are delivered to late endosomes and finally degraded after fusion with lysosomes. During these processes, endosomes suffer translocation from the cell periphery to the perinuclear region, which is accompanied by fusion, invagination, tubulation, and membrane fission events. As expected, complex cellular signaling processes tightly control the endocytic pathway at different steps. Several GTPases, such as Rab7, Rab24 and Arl8b, associated with their effectors RILP, FYCO1 and PLEKHM1, are crucial for endosome trafficking. Here, we examine the current knowledge concerning endosome-lysosome fusion, emphasizing the main protein interactions related to this process.