Membrane contact sites are regions of close apposition between organelles that have emerged as platforms to transfer small molecules. Many compartments of the endo-lysosomal system form contacts with the endoplasmic reticulum (ER), but little is known about how they are regulated. Here I discuss novel mechanisms underlying contact site form and function. Contact between endosomes and the ER requires the calcium mobilising messenger NAADP, its target endo-lysosomal ion channel, TPC1 and associated local calcium fluxes. Reducing endosomal contacts perturbed endo-lysosomal morphology and impaired EGF-mediated signalling pathways. Additionally, I discuss the role of VAP proteins in regulating lysosome-ER contacts and calcium signalling through TRPML1, another endo-lysosomal ion channel defective in the lysosomal storage disease mucolipidosis IV. Therefore, membrane contact sites between the endocytic pathway and ER emerge as calcium signalling hubs.