It is now well accepted that a significant genetic component governs host susceptibility to different infectious diseases. As the Toll-like receptors (TLRs), together with their co-receptors and their downstream signalling partners, play such a crucial role in pathogen recognition and subsequent activation of the host immune response, any genetic mutation (polymorphism) that alters the protein structure and in so doing affects the ability of the TLRs or their co-receptors to bind to their associated pathogen-associated molecular patterns (PAMPs) will likely affect host susceptibility towards infection. Examination of the TLR signalling cascade suggests the existence of several bottlenecks or rate-limiting steps, obvious ones being at the level of the receptors, the adaptor proteins, TNF receptor-associated factor 6 (TRAF6), as well as at the IκB/NF-κB interaction point. Mutations to these downstream members might confer either resistance or increased susceptibility, depending on their nature. Indeed, it has been demonstrated time and again that natural variation in some of the molecules mentioned above does affect differential susceptibility to infectious diseases (e.g. invasive bacterial infections, tuberculosis, and malaria) specific to the binding spectrum of the TLRs involved.