Since the 1950s, great efforts have been made to develop antiviral agents against many infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), human cytomegalovirus (HCMV), herpes simplex virus (HSV), and varicella-zoster virus (VZV). Among the list of nearly 106 antiviral agents approved in the past five decades, Prof. Erik De Clercq has contributed to the development of 7 antiviral drugs: tenofovir disoproxil fumarate (Viread®) for HIV and HBV treatment, tenofovir alafenamide (Vemlidy®) for HIV and HBV treatment, brivudine (Zostex®) for HSV-1 and VZV treatment, valacyclovir (Valtrex®) for HSV and VZV treatment, adefovir dipivoxil (Hepsera®) for HBV treatment, stavudine (Zerit®) for HIV treatment, and cidofovir (Vistide®) for treating HCMV retinitis in AIDS patients. In addition to the above antiviral drugs, his contributions include two anti-cancer drugs: rabacfosadine (Tanovea®-CA1) for canine lymphoma and plerixafor (Mozobil®) for multiple myeloma and non-Hodgkin’s lymphoma. These achievements are driven by his life-long passions for antiviral research and successful collaborations worldwide. To honor the 80th birthday of Prof. Erik De Clercq, this study highlights his scientific achievements and the importance of life-long passions and collaborations in the success of antiviral research and drug development.