In summary, this study demonstrated that NAADP, a CD38‐derived lysosomal Ca2+ messenger, is essential for the free cholesterol efflux from lysosomes in mouse macrophages and that the deficiency of CD38 gene leads to lysosome free cholesterol segregation, lysosomal lipidosis and atherosclerosis, a work model with all major findings have been incorporated into a diagram (Fig. 10). Here, CD38 is linked to atherosclerosis.