Summary: The lysosomal pathway digests material received by two main routes, phagocytosis and autophagy. Cells use phagocytosis to ingest extracellular particles by invaginations of the plasma membrane. In autophagy, a double membrane structure isolates portions of the cytoplasm to target it for degradation. During infection, phagocytes use both of these cellular functions to restrict microbial replication and at the same time to orchestrate an appropriate response against the invader. Toll-like receptor recognition of a pathogen initiates an innate immune response against the pathogen that includes production of inflammatory cytokines, upregulation of costimulatory molecules to prime an adaptive immune response, and activation of phagocytosis and autophagy. Signaling through this family of receptors also produces a hybrid response in which proteins that participate in autophagy are recruited to phagosomes, resulting in expedited microbial elimination. In this review, we discuss recent views on how Toll-like receptors direct microbes to final destruction by regulating the different pathways that lead to the lysosome.