Lysosomal cysteine cathepsins are a family of proteases that are involved in a myriad of cellular processes from proteolytic degradation in the lysosome to bone resorption. These proteins mature following the cleavage of a pro-domain in the lysosome to become either exo- or endo-peptidases. The cathepsins B, C, L, S and Z have been implicated in NLRP3 inflammasome activation following their activation with ATP, monosodium urate, silica crystals, or bacterial components, among others. These five cathepsins have both compensatory and independent functions in NLRP3 inflammasome activation. There is much evidence in the literature to support the release of cathepsin B following lysosomal membrane degradation which leads to NLRP3 inflammasome activation. This is likely due to a hitherto unidentified role of this protein in the cytoplasm, although other interactions with autophagy proteins and within lysosomes have been proposed. Cathepsin C is involved in the processing of neutrophil IL-1β through processing of upstream proteases. Cathepsin Z is non-redundantly required for NLRP3 inflammasome activation following nigericin, ATP and monosodium urate activation. Lysosomal cysteine cathepsins are members of a diverse and complementary family, and likely share both overlapping and independent functions in NLRP3 inflammasome activation. •Multiple cathepsins are involved in NLRP3 inflammasome activation; the context of activation may determine which cathepsins—or whether cathepsins—are involved.•Cathepsins B, C, L, S, Z may share overlapping or compensatory functions in NLRP3 inflammasome activation.•Cathepsin B has been implicated in inflammasome activation using compounds that induce lysosomal membrane permeabilization and may involve negative regulation of autophagy.•Cathepsin C has been reported to activate neutrophil serine proteases which cleave IL-1β independently of caspase-1.•Cathepsin Z is involved in NLRP3 inflammasome activation independently of lysosomal membrane permeabilization.