Male infertility is a complex and multifactorial condition affecting up to 12% of men worldwide, with genetic factors playing a key role in all etiological categories. Current routine genetic tests include karyotyping, Y chromosome microdeletion analysis, and targeted multigene panel sequencing in selected phenotypes, e.g., congenital hypogonadotropic hypogonadism. Following a complete diagnostic workup, including the above genetic tests, approximately 50% of cases remain idiopathic. The advent of Whole Exome Sequencing (WES), has significantly enhanced our ability to uncover novel monogenic causes of male infertility and to redefine the diagnostic evaluation of infertile men. This chapter explores the dual role of WES as both a diagnostic strategy and a discovery tool, with a focus on the implementation of WES-derived virtual gene panels (VGPs). These panels allow for dynamic, cost-effective reanalysis and are increasingly applied in clinical genetics. We discuss about gene-disease relationships (GDRs), highlight validated genes with diagnostic utility, and pinpoint emerging candidate genes across qualitative and quantitative spermatogenic disorders. Finally, we examine the clinical implications of genetic diagnosis, emphasizing the role of personalized genetic counseling in optimizing assisted reproductive outcomes and informing short- and long-term health risks for patients and their offspring.