The development of broad-spectrum antiviral agents has recently become a major thrust area in the field of virology, and received enormous attention in the pharmaceutical industry worldwide. Much progress has been made to substantially extend the limitations of current antiviral therapy drugs, which are mostly pathogen-specific. Breakthroughs were made in establishing fundamental understanding of the underlying biochemical mechanisms. Part of the research results have been implemented for practical applications. The present review addresses the state-of-the-art knowledge, prospective applications, and challenges for the development of broad-spectrum antiviral agents. Detailed models of agent targets to virus entry and infection, and host cell defense are given. Finally, future research needs and opportunities are discussed.