•Many viruses have evolved to utilize the host UPS for their own benefit.•Viruses subvert the UPS to maintain optimal level/function of viral proteins.•Viruses exploit the UPS to degrade host proteins which impede viral growth.•The UPS serves as an important host anti-viral defense mechanism.•The UPS is inhibited by some viruses to prevent viral clearance. The ubiquitin–proteasome system (UPS) plays a central role in a wide range of fundamental cellular functions by ensuring protein quality control and through maintaining a critical level of important regulatory proteins. Viruses subvert or manipulate this cellular machinery to favor viral propagation and to evade host immune response. The UPS serves as a double-edged sword in viral pathogenesis: on the one hand, the UPS is utilized by many viruses to maintain proper function and level of viral proteins; while on the other hand, the UPS constitutes a host defense mechanism to eliminate viral components. To combat this host anti-viral machinery, viruses have evolved to employ the UPS to degrade or inactivate cellular proteins that limit viral growth. This review will highlight our current knowledge pertaining to the different roles for the UPS in viral pathogenesis.