Viruses have evolved efficient strategies to overcome cellular membranes and transfer nucleic acid into a host cell. This property is being exploited in gene therapy which has the goal of delivering therapeutic genes into a patient tissue in order to achieve a clinically relevant effect. An interesting target for virus-mediated gene transfer is the immune system. In fact, the first human gene therapy trial performed involved the implantation of autologous bone marrow cells transduced ex vivo with gamma retrovirus vectors expressing adenosine deaminase in a patient with severe combined immunodeficiency. More recently, targeting transgene expression to dendritic cells (DCs) has become a promising strategy for directing the immune system towards immunity or tolerance. DC targeting has been achieved on a transcriptional level by using DC-specific promoters or by retargeting the tropism of the virus vectors. For example, we and others have developed strategies that support antigen-specific immune tolerance by transducing hematopoietic stem cells with lentivirus- or gamma retrovirus- vectors that transcriptionally target antigen expression to DCs. This review discusses the state of the art of vector-targeting to DCs in preclinical as well as clinical trials.