Lipid rafts are envisaged as islands of highly ordered saturated lipids and cholesterol that are laterally mobile in the plane of the plasma membrane. Lipid rafts are thought to provide a means to explain the spatial segregation of certain signalling pathways emanating from the cell surface. They seem to provide the necessary microenvironment in order for certain specialised signalling events to take place- such as the innate immune recognition. The innate immune system seems to employ germ-lined encoded receptors, called pattern recognition receptors (PRRs) in order to “sense” pathogens. One family of such receptors are the Toll like receptors (TLRs), which are the central “sensing” apparatus of the innate immune system. In recent years, it has become apparent that TLRs are recruited into membrane microdomains in response to ligands and these constitute signalling platforms, which transducer singals that lead to innate immune activation. In this chapter will review all past and current literature concerning recruitment of TLRs into lipid rafts and how this membrane compartmentalization is crucial for innate immune responses.