Bacterial DNA and synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODNs) are strong activators of both innate and specific immunity, driving the immune response towards the Th1 phenotype. CpG-ODNs have been successfully used in several experimental models of allergies or infections and are now entering clinical trials for these diseases. In this review, we will focus on their potential applications in cancers. CpG-ODN can be used alone to activate locally the innate immunity and trigger a tumor-specific immune response, overcoming the need for identification of a relevant tumoral antigen. Other promising approaches combined CpG-ODN with tumor antigens, monoclonal antibodies or dendritic cells. Preclinical models have shown impressive results and several clinical trials are on-going worldwide. So far, the toxicity observed in humans appeared limited, and objective responses have been observed in a few patients. In malignant gliomas, intra-tumoral injections of CpG-ODN represent a practical approach. Indeed, human gliomas display a locally invasive pattern of growth and rarely metastasize, making local treatment clinically relevant.