Endosomes are important organelles for the transport and sorting of endocytosed cargo but also for other functions, such as signal transduction, regulation of metabolism and stress response. The multifunctional activity of endosomes can be appreciated by manipulating its molecular machinery. Rab5 is necessary for the biogenesis of the entire endo-lysosomal pathway in vivo. It regulates the specificity and directionality of endosome fusion via the recruitment of tethering effectors that lead membranes to dock and fuse. EEA1 is a tethering factor that bridges a Rab5-positive early endosome with another vesicle harbouring Rab5. Upon binding, Rab5 induces an allosteric conformational change on EEA1, from extended to flexible, generating an entropic collapse force that helps pulling the membranes together. This means that the function of Rab proteins goes beyond effector recruitment, regulating membrane recognition and mechanics leading to organelle fusion. Besides transport, loss of Rab5 and of the endosomal pathway leads to alterations in sugar and lipid metabolism which reflect novel functions of the endosomal system in the regulation of metabolic pathways. Finally, we have now discovered a novel Rab5-dependent cyto-protective pathway involving endosomes and mitochondria in response to stress. Dysfunction of this pathway has implications for amyotrophic lateral sclerosis (ALS) and possibly other neurodegenerative diseases.