Lysosomes are essential catabolic organelles with an acidic lumen and dozens of hydrolytic enzymes. The detrimental consequences of lysosomal leakage have been well known since lysosomes were discovered during the 1950s. However, detailed knowledge of lysosomal quality control mechanisms has only emerged relatively recently. It is now clear that lysosomal leakage triggers multiple lysosomal quality control pathways that replace, remove, or directly repair damaged lysosomes. Here, we review how lysosomal damage is sensed and resolved in mammalian cells, with a focus on the molecular mechanisms underlying different lysosomal quality control pathways. We also discuss the clinical implications and therapeutic potential of these pathways.