Abstract: For a long time since their discovery by Christian de Duve in the 1950s, lysosomes have been referred to almost exclusively as passive garbage bags; the endpoint in the degradation of intra- and extracellular cargo. The catabolic function of lysosomes is accomplished by an array of more than 60 acid hydrolases, which together break down a wide variety of biological macromolecules, including proteins, lipids, carbohydrates, and nucleic acids, for reutilization in the metabolic processes of the cell. For their optimal function, these enzymes require an acidic intraluminal pH of ~4.5, which is maintained by the joint action of a proton pump, the vacuolar H+-ATPase, and several ion channels embedded in the lysosomal limiting membrane. Nowadays, lysosomes are envisioned as complex signaling hubs, integrating diverse stimuli about the cell’s metabolic status to coordinate different adaptive responses (Ballabio and Bonifacino, 2020). The lysosome can also induce cell death signals in response to certain conditions, such as infections and treatment with lysosomotropic drugs, which leads to lysosomal membrane permeabilization (LMP) and the release of cathepsins, resulting in lysosomal-mediated cell death (Figure 1A, left). Lysosomes are also important intracellular calcium reservoirs. Lysosomal calcium plays essential functions in several cellular processes, such as lysosomal fusion with other vesicles, lysosomal biogenesis, and exocytosis (Figure 1A, right). In addition, lysosomal calcium is critical for lysosomal acidification, probably through the establishment of physical contacts with the endoplasmic reticulum. As a signaling molecule, calcium release from the lysosome through the transient receptor potential cation channel, mucolipin subfamily member 1 (TRPML1) activates the autophagic signaling pathway through the transcription factor EB (TFEB), which upregulates genes involved in autophagy and lysosomal biogenesis. Only three main types of lysosomal Ca2+ channels have been identified: the transient receptor potential channels of the mucolipin family, two-pore channels (TPC), and the trimeric Ca2+ two-transmembrane channel P2X4. However, the lysosomal membrane comprises dozens of integral and peripheral proteins of unknown functions. The identification of new regulators of lysosomal biology is essential to better understand the role of lysosomes in the global regulation of adaptive and pro-dead responses, and their close connection to cell metabolism.