Exogenous and endogenous fine particles such as environmental materials (e.g., silica, asbestos, alum), toxic protein aggregates (e.g., α-synuclein, amyloid-β), and endogenous crystals (e.g., cholesterol crystals, uric acid crystals) are internalized into the cell by the endocytic pathway or phagocytosis. Because lysosomes are the terminal compartments of these pathways, lysosomes are known to be damaged by exocytosed extracellular fine particles. Lysosomal membrane damage allows the leakage of the lysosomal contents such as cathepsins, H+, Ca2+, and iron into the cytosol, which is harmful to the cell. Numerous studies have suggested that lysosomal damage is tightly associated with toxicity of exogenous particles, inflammatory responses, and diseases including those involving neurodegeneration. To preserve lysosomal integrity, cells have several mechanisms for the repair or elimination of compromised lysosomes collectively called the “lysosomal damage response”. This review summarizes recent findings on the responses to lysosomal damage, focusing on extracellular fine particles.