Oncolytic virus therapy (OVT) is a promising treatment modality for cancer that uses tumor-specific defects to target cancer cells selectively. An increasing number of replicating viruses has been demonstrated to cure cancer in a diverse set of animal models. Accordingly, many such viruses have entered the clinic, with several phase III clinical trials having recently been approved or initiated. As with most modalities that target cancer, which is a disease characterized by pronounced cellular heterogeneity and genetic instability, it is anticipated that the efficacy of OVT will benefit from combination therapy. During the past 5 years, significant efforts have been invested in evaluating the combination of OVT and existing chemotherapies, as well as rationally designing chemical-OVT combinations. This review provides an update on these two approaches to augmenting OVT, and suggests that unbiased, high-throughput genetic and chemical screening technologies may both compliment and offer several advantages when combined with these approaches in the pursuit of effective chemical-OVT combinations for the treatment of cancer.