After leaving the CDC, Moore served briefly as a New York City epidemiologist but quit to search for new human viruses with his wife, Yuan Chang who was then a newly appointed assistant professor at Columbia University.

Despite having no research funding, Moore and Chang used a new molecular biology technique, representational difference analysis, to search for a virus causing Kaposi's sarcoma, the most common malignancy among AIDS patients.

[7] In 1994, they discovered a new human herpesvirus, KSHV, in a KS tumor and along with several collaborators showed that it was the etiologic agent of Kaposi's sarcoma, primary effusion lymphoma, and some forms of multicentric Castleman's disease.

They subsequently sequenced KSHV,[11] identified oncogenes encoded by the virus,[12] demonstrated transmission during transplantation and developed diagnostic tests to detect infection.

Chang and Moore jointly developed a new technique to find human tumor viruses called digital transcriptome subtraction (DTS).