Recently, novel cancer immunotherapy approaches have gained rising interest. While chronic inflammation has been defined as a major hallmark of malignancy, acute and targeted inflammation may be able to stimulate the immune system to treat illnesses, such as cancer. Toll-like receptors (TLRs) are innate immune receptors that act as a bridge between innate and adaptive immune systems. These receptors can be expressed both within cellular compartments and on the cellular surface. For a long time, TLR binders have been used as adjuvants for conventional vaccines; Indeed, it appears that they can exert actions in promoting the efficacy of cancer immunotherapy. The application of approaches targeting TLRs to treat cancer now extends to more novel approaches of chimeric antigen receptor (CAR) T-cell and monoclonal antibodies. The aim of this chapter is to provide an overview on TLRs’ molecular pathways in immune cells, the influence of TLR stimulation in cancer immunotherapies, production of TLRs in various cancers, and ultimately, its role in mediation of tumor microenvironment and cancer progression.