Viral suppressors of RNA silencing (VSRs) are proteins that interfere with antiviral defense mechanisms and enhance infection. For plant viruses, VSRs can be encoded in viral genomes and satellite molecules and play an important role in the virus life cycle and in overcoming host defenses. However, a comprehensive review on multifunctionality of VSRs and their role in the spread of plant diseases worldwide has not been performed. Here, we aim to synthesize the current understanding of the role of VSRs in the pathogenesis of Solanaceous plants, a family that includes many crop and medicinal plants. We focus on three key areas: (1) the diversity of VSRs and the mechanisms used to suppress anti-viral defense, (2) the role of VSRs in viral pathogenesis beyond interfering with host RNA-silencing, and (3) the co-evolution between VSRs and plant host proteins. Additionally, we describe how VSRs promote the development of diseases by altering various steps in the process of viral pathogenicity by inducing counter-defense mechanisms. Specifically, a substantial body of evidence suggests that VSRs induce suppression of antiviral silencing, abrogation of phytohormone signaling, and R-gene-mediated host defense. Furthermore, we discuss how identifying and characterizing novel interactions between VSRs and Solanaceous host factors may be leveraged for developing sustainable pathogen and pest management strategies.