Protein trimerization plays a critical role in numerous biological processes, including structural stabilization, molecular signaling, and viral entry. This chapter examines the molecular mechanisms underlying trimerTrimer formation—such as hydrophobic interactionsHydrophobic interactions, hydrogen bondingHydrogen bonding, and covalent modifications and highlights their relevance to virology and anti-viral drug development. A central focus is the role of trimeric viral proteins in membrane fusion and capsid assembly, particularly those from flaviviruses, HIV-1, and SARS-CoV-2SARS-CoV-2. One key example is glycoprotein BGlycoprotein B (gB), the conserved Class III fusion protein found in herpesvirusesHerpesvirus. gB functions as a trimerTrimer and undergoes a dramatic conformational shift from a metastable pre-fusion state to a stable post-fusion form. This transition, initiated by upstream glycoproteins such as gH/gL and gD (or gp42 in Epstein-Barr virus), facilitates viral membrane fusion with host cells. Structural analyses have shown that gB’s five-domain architecture and trimeric configuration are highly conserved across herpesvirusHerpesvirus families, making it a compelling target for antiviral therapies and vaccineVaccine development. Advances in cryo-electron microscopyCryo-electron microscopy and molecular dynamicsMolecular dynamics simulations have further illuminated the behavior of trimeric proteinsTrimeric proteins, informing the design of vaccinesVaccine, small-molecule inhibitors, and engineered trimeric scaffolds for drug delivery. A deeper understanding of trimerization mechanisms offers significant potential for innovation in antiviral strategies, precision medicine, and bioengineering.