Direct infection of tumor cells with viruses transfering protective or therapeutic genes-a frequently used procedure for production of tumor vaccines in human gene therapy-is often limited by the number of tumor cells that can reliably be infected, as well as by issues of selectivity and safety. In this review, we describe an efficient, selective, and safe way of infecting human tumor cells with a natural virus with interesting pleiotropic immune stimulatory properties, the avian paramyxovirus Newcastle disease virus (NDV). Advantages of this virus are its good cell-binding properties, its selective replication in tumor cell cytoplasm, which is independent of cell proliferation, and its relative safety. Most important for its use as an adjuvant in human cancer vaccine are its ability to introduce T-cell costimulatory activity, to prevent anergy induction, and to induce locally chemokines (eg, RANTES, IP-10) and cytokines (eg, interferon alpha, beta [IFN-alpha, beta] and tumor necrosis factor-alpha [TNFalpha]) that affect T-cell recruitment and activation. A further development consists of attachment-via NDV-derived hemagluttinin-neuraminidase (HN) membrane-anchoring molecules-of universal defined bispecific reagents such as T-cell-activating anti-CD28 antibodies. Finally, we summarize the status of our clinical studies with the autologous virus modified live cell vaccine (ATV)-NDV.