The application of cancer gene therapy has heretofore been restricted to local, or locoregional, neoplastic disease contexts. This is owing to the lack of gene transfer vectors, which embody the requisite target cell selectivity in vivo required for metastatic disease applications. To this end, we have explored novel vector engineering paradigms to adapt adenovirus for this purpose. Our novel strategy exploits three distinct targeting modalities that operate in functional synergy. Transcriptional targeting is achieved via the hROBO4 promoter, which restricts transgene expression to proliferative vascular endothelium. Viral binding is modified by incorporation of an RGD4C peptide in the HI loop of the fiber knob for recognition of cellular integrins. Liver sequestration is mitigated by ablation of factor X binding to the major capsid protein hexon by a serotype swap approach. The combination of these technologies into the context of a single-vector agent represents a highly original approach. Studies in a murine model of disseminated cancer validated the in vivo target cell selectivity of our vector agent. Of note, clear gains in therapeutic index accrued these vector modifications. Whereas there is universal recognition of the value of vector targeting, very few reports have validated its direct utility in the context of cancer gene therapy. In this regard, our article validates the direct gains that may accrue these methods in the stringent delivery context of disseminated neoplastic disease. Efforts to improve vector targeting thus represent a critical direction to fully realize the promise of cancer gene therapy.