Glucocerebrosidase (GCase) is manufactured and N-glycosylated in the rough endoplasmic reticulum (ER) and folded by intracellular chaperones (ER Hsp70 family member BiP/Grp78) into a functional conformation. After association with lysosomal integral membrane protein (LIMP), GCase undergoes further processing and packaging in the Golgi apparatus and is delivered to the lysosome where, in association with an essential cofactor, saposin C, and anionic phospholipids, it catalyzes the hydrolysis of glucocerebroside (GL-1) to ceramide and glucose. Mutant GCases fail to properly fold in the ER and trigger the unfolded protein response, ubiquitination, and disassembly in the proteasome. However, some mutant GCase with variably residual hydrolytic activity does traffic to the lysosome. ERT is delivered directly to the lysosome where it augments the qualitatively and quantitatively deficient mutant GCase activity. GL-1 is synthesized de novo on the cytosolic surfaces of the Golgi and, via a detour to the smooth ER, is returned to the Golgi lumen where it is processed into more complex glycosphingolipids. SRTs slow the synthesis of GL-1 by the inhibition of ceramide glucsyltransferase. However, much of the GL-1 that is stored in Gaucher macrophages is derived exogenously, secondary to lysosomal degradation of senescent blood cells. Professional illustration by Patrick Lane, ScEYEnce Studios.