The human gut is the largest interface between the external environment and the human body. The gut immune system should, therefore, be able to differentiate between the normal nonpathogenic residents of the gut and any pathogenic invaders. This differentiation is based on the tiny molecular differences on the cell surfaces of the microorganisms. The first interaction between the pathogen and the immune system is thus crucial. This sensing by the immune system is done by a family of pattern recognition receptors (PRRs), among which the most important are the toll-like receptors (TLRs). The distribution of TLRs in the different areas of gastrointestinal tract (GIT)c depends on the type of commensal residents of that area. The interaction between gut microbiota and TLRs on one hand restricts the colonization of particular microbes to a particular area and on the other hand, dictates the type of TLRs distributed in a particular gut location. This interaction promotes tolerance to the normal residents, but the same time enables the gut associated lymphoid tissue to be able to detect any foreign and potentially pathogenic invaders. The numbers and polarization of the underlying populations of macrophages and dendritic cells beneath the Paneth and M-cells depends upon the trophic factors released by the intestinal epithelial cells as a result of signaling through TLRs. The interaction between these two players is not only immune related, but also has many metabolic consequences. The link between inflammation and many metabolic diseases has been consistently reported. The role of TLRs in the metabolic reprogramming of immune cells is crucial which facilitates the conservation of metabolic energy to be harnessed for immune functions. The knowledge on the TLR-microbiota interaction, its role in immune and metabolic functions, and the results of manipulations with this interaction are the subject of this review.