The identification of the pathogen-associated molecular recognition patterns (PAMPs) recognition receptors for innate immunity, most notably the Toll-like receptors (TLRs), has sparked great interest in therapeutic manipulation of the innate immune system. We apply computational methodologies, such as MD simulations and protein-protein docking, to the study of the molecular mechanisms involved in the TLRs functionality, and the recognition by PAMPs, such as natural lipopolisaccharides and lipopeptides. We also make use of ligand-protein docking and virtual screening as a source of new compounds able to modulate the TLRs behaviour with possible therapeutic applications in infection, inflammation, cancer, and neurodegenerative diseases, among others.