Monkeypox is an emerging viral zoonosis with symptoms similar to those observed in smallpox patients, although less severe. Since the global eradication of smallpox in 1980, monkeypox has emerged as the most important orthopoxvirus in humans. The Advisory Committee on Variola Virus Research (ACVVR) which meets annually to oversee smallpox research has highlighted the importance of diagnostics that could distinguish between variola and other strains of orthopoxviruses, including monkeypox virus. The ACVVR encourages the positive effects of current smallpox research on all orthopoxviruses, specifically monkeypox, such as the development of diagnostic tools.