Oncolytic viruses are capable of selective replication in malignant cells and therefore offer levels of potency and specificity that are potentially far higher than conventional treatments for cancer. New developments in vector design and administration regimes are gradually moving toward systemic applications, with the ultimate aim of treating common cancer indications that present with multiple disseminated metastases. Nevertheless, the delivery of therapeutic quantities of viruses via the blood stream to target cells in humans or stringent animal models remains a challenging task: the relatively large size of virus particles restricts their penetration into tissues, and defines their biodistribution and clearance kinetics. In addition, multiple interactions with blood cells and serum proteins can impact on vector bioavailability. Finally, the immunological response to virus administration can vary considerably from patient to patient and even more so between species, making it difficult to draw accurate clinical predictions from model systems. Unfortunately, the extensive experience gained from the application of low-molecular-weight therapeutic drugs provides little insight into the behavior of viral therapeutics administered into the blood stream. In this review, the fate of virus particles following intravenous delivery is described, followed by an assessment of the latest approaches to control and improve vector delivery.