The family of the toll-like receptors comprises a minimum of 10 members identified in humans so far. These transmembrane receptors act as important signaling intermediates between the host and the invading pathogens. The following review describes the complexities encountered by researchers studying toll-like receptor (TLR) expression changes during bacterial infections. Mutations in some of the TLRs, most prominently TLR4 and TLR2, have been associated with increased susceptibility to infectious diseases. While it is tempting to correct the phenotypic effect of such mutations, in vitro and in vivo research has shown that TLR activity and function comprises a complex regulatory network. Heterodimer formation, synergy, and cross-tolerance have previously been described. More recently, interdependence of TLR2 and TLR4 expression has been identified. In addition, TLR expression follows a specific timeline that may be dependent on the invading pathogen. Lastly, mutations in invading pathogens have been shown to alter the expression profile of TLR2 and TLR4, indicating that therapies against bacterial pathogens will have to target multiple TLRs. Despite the complexities involved in TLR function, the significant progress made in our understanding of the role these proteins play in human diseases also indicates their potential value as therapeutic agents.