Over the years, there has been an exponential increase in the number of gene therapy approaches that are under investigation for the treatment of cancer. This can be attributed to our growing understanding of the molecular mechanisms that contribute to the onset and maintenance of cancer as well as to the development of gene delivery vectors. In this review, we will focus on the use of lentiviral vectors (LVs) in immuno gene therapy of cancer, as these efficacious gene delivery vehicles have come to the fore front because of their many attractive features. LVs have been successfully applied to generate potent dendritic cell based anti-cancer vaccines and to deliver cancer-specific receptors to T-cells. Moreover, LVs are under investigation for the modulation of cancer cells. We will describe various strategies of this 'genuine' cancer gene therapy, amongst which transfer of suicide genes, modulation of pro- and anti-apoptotic molecules, strategies to optimize chemo- and radiotherapy, expression of molecules that affect angiogenesis or affect the immunogenicity of tumor cells. These will be discussed in view of our current knowledge of tumor immunology. Finally we will discuss some important issues and future directions to push the field forward.