Virus-related mortality and morbidity are due to cell/tissue damage caused by replicative pressure and resource exhaustion, e.g., HBV or HIV; exaggerated immune responses, e.g., SARS-CoV-2; and cancer, e.g., EBV or HPV. In this context, oncogenic and other types of viruses drive genetic and epigenetic changes that expand the tumorigenic program, including modifications to the ability of cancer cells to migrate. The best-characterized group of changes is collectively known as the epithelial–mesenchymal transition, or EMT. This is a complex phenomenon classically described using biochemistry, cell biology and genetics. However, these methods require enormous, often slow, efforts to identify and validate novel therapeutic targets. Systems biology can complement and accelerate discoveries in this field. One example of such an approach is Boolean networks, which make complex biological problems tractable by modeling data (“nodes”) connected by logical operators. Here, we focus on virus-induced cellular plasticity and cell reprogramming in mammals, and how Boolean networks could provide novel insights into the ability of some viruses to trigger uncontrolled cell proliferation and EMT, two key hallmarks of cancer.