Toll-like receptors (TLR) constitute one of the components of the innate immunity, based on the recognition of conserved molecular structures found in large groups of pathogens. A total of 11 Toll-like receptors have now been described in humans. Toll-like receptors are expressed on virtually every type of cell, including immunocompetent cells. Ligand binding triggers signaling cascade that leads to the induction of key proinflammatory mediators that contribute to an immune response. Additionally, TLR induction results in the activation and shaping of the adaptive immune reaction. TLRs have also been identified as potential therapeutic targets. Their capability to augment antigen presentation or induce the expression of target molecules has rendered them plausible therapeutic agents. Recently, synthetic ligands have been described and some of them have already been established in the treatment of skin cancer (TLR7 agonist) and as anti-hepatitis B virus vaccine adjuvants (TLR4 agonists). Furthermore, many clinical trials on TLR agonists as potent enhancers of antitumor response in solid tumors are currently on going. Considering that TLRs are widely expressed on transformed cells of the immune system (from blasts to memory cells), they may become a promising candidate for developing effective therapeutic options in hematologic malignancies as many in vitro studies have shown the intact functionality of TLRs in transformed cells. Moreover, a few clinical trials investigating the safety of synthetic TLR agonists are currently ongoing. Therefore, it is necessary to conduct further studies in order to assess the clinical relevance of the applicability of TLR-aimed therapy in the treatment of hematologic malignancies.