Infectious diseases, caused by bacteria, viruses, fungi, protozoa, or parasites are among the leading causes of death worldwide. The efficacy of all current anti-infectives is threatened by the spread of drug resistance factors, with some already made ineffective, and, as a result, there is a pressing need for a new pipeline of robust anti-infective drugs. In silico approaches, such as virtual high throughput screening and de novo structure-based rational drug design, have been established as powerful tools in drug discovery. In this review, we explore the exciting opportunities for antimalarial, antiviral, and antibacterial drug discovery arising from the new paradigm of structure-based drug design.