Intracellular Gal-8 mediates autophagy through binding to glycans of ruptured vacuolar membranes and the autophagy receptor NDP52 to initiate the formation of autophagosomes. Autophagy is considered as inhibitory to the action of inflammasomes that promote the generation of selected cytokines. Gal-8 binding to exposed luminal glycans of damaged lysosomal membranes inactivates mTOR. Direct in vitro interactions of intracellular Gal-8 with K-Ras, inhibit K-Ras activity and abrogates ERK signaling pathway. ERK and mTOR stimulate the NF-κB pathway, therefore, their inhibition by intracellular Gal-8 is expected to dampen cytokine/chemokine expression and secretion. Gal-8 also functions extracellularly. Extracellular Gal-8 binds to a complex of cell surface receptors that include LRP1, uPAR, and MRC2; CD44 and members of the integrin family. Their ligation triggers many signaling cascades including AKT, ERK, and JNK that stimulate the NFkB signaling pathways that converge upon cytokine/chemokine production and secretion. Activation of specific cytokines is presumably mediated by different signaling pathways. For example, RANKL expression in osteoblasts is mediated by the ERK pathway, whereas expression of SDF-1 in the same cells, is triggered by JNK. The secreted cytokines serve as chemo-attractants of cancer cells and as potential inducers of a ‘cytokine storm’. The interplay between the actions of intracellular vs. extracellular Gal-8 deserves further elucidation.