Over the past decade, immunotherapy has emerged as a promising alternative form of cancer treatment with the potential to eradicate tumour metastasis. However, its curative potential is in general limited by peripheral tolerance mechanisms and the elimination of self-reactive T cells via thymic negative selection. Unlike infectious challenges, tumour cells arise endogenously, and therefore the majority of tumour antigens are recognized as self. Under appropriate conditions, however, tumour reacting T cells can be activated through a mechanism of molecular mimicry, which involves the recognition of cross reactive foreign antigens mimicking tumour antigens. Moreover, dendritic cells can be reprogrammed by RNA interference to present self-antigens and activate anti-tumour T cells. This review highlights some of the strategies used to break self-tolerance against solid and blood tumour cells. Also, the possibility of reprogramming DC and/or lymphocyte functions using small interfering RNAi (siRNA) is discussed.