Toll-like receptors (TLRs) are a group of transmembrane receptors that recognize molecular motifs of pathogen origin and activate immune response. Although TLRs were first identified in immune system cells, recent studies show they can also be expressed in tumor cells. TLR3 recognizes dsRNA or its synthetic ligand poly (I: C) and is responsible primarily for the defense against viral infections. Recent studies showed that TLR3 can trigger apoptosis in cancer cell. Furthermore, other dsRNA binding receptors (MDA5 and RIG-I), localized in cytoplasm, can also bind poly (I: C) and therefore contribute to this effect. With TLR3’s capacity to induce apoptosis and activate the immune system at the same time, TLR3 ligands are an attractive therapeutic option for treatment of cancer. Novel therapies include combining poly (I: C) with other components such as chemotherapeutics, apoptosis enhancers, other TLR ligands and peptides activating the immune system. Slightly modified TLR3 agonists (Ampligen®, Hiltonol®, poly IC-LC) are already being used in clinical studies for cancer therapy as single agents or in combination with other drugs. On the other hand, latest studies forewarn that TLR3 activation can also have tumor promoting role so it is crucial to identify the terms by which TLR3 has pro-tumor/anti-tumor effect in order to safely implement TLR3 ligand based therapy into clinical trials.