Toll-like receptor (TLR) agonists are potent activators of innate immune responses, activating dendritic cell (DC) maturation and inflammatory cytokine secretion by innate immune cells and as a consequence they promote adaptive immune response when coadministered with foreign antigens. There is also some evidence from mouse models that TLR ligands can help to break tolerance to self-antigens and promote immune responses to tumour antigens. Therefore, they have been exploited as adjuvants for tumour vaccines or as immunotherapeutics against cancer. Clinical evaluation of TLR agonists has resulted in a licensed immunotherapeutic for basal cell carcinoma, but there have also been disappointing results from clinical trials, with one pharmaceutical company recently halting its clinical programme. A major obstacle to the development of any active immunotherapeutic approach to cancer is the immunosuppressive environment of the growing tumour, including the induction of tolerogenic DCs and regulatory T (Treg) cells, which suppress the development of protective effector T-cell responses. This can be compounded by the use of TLR ligands as immunotherapeutics. A problem with TLR agonists that has not been fully appreciated is that they can generate suppressive as well as inflammatory responses in innate immune cells and can promote the induction of regulatory as well as effector T cells. This is part of a normal mechanism for limiting collateral damage during infection or sterile inflammation, but can constrain their ability to induce protective antitumour immunity, especially in the immune suppressed environment of the tumour. Alternatively, manipulating the TLR-activated innate immune responses to selectively blocking immunosuppressive arm, as well as that induced by the tumour, may hold the key to enhancing their efficacy as tumour immunotherapeutics and as adjuvants for cancer vaccines.