Genetic factors are responsible for about 20–25% of severe male factor infertility and may affect both gametogenic and endocrine functions of the testis or may cause the congenital absence of vas deferens. Testing for chromosomal anomalies (karyotype and Y chromosome microdeletions) is performed in all patients affected by moderate or severe oligozoospermia and azoospermia, whereas mutation screening in candidate genes is indicated in specific disease conditions. All the above-mentioned analyses aim at the identification of genetic factors showing a cause-effect relationship with the given phenotype, and they are part of the diagnostic work-up of infertile men. During the last 20 years, active research has been carried out in order to identify novel candidate genes and genetic risk factors for impaired sperm production. Despite efforts, the only genetic risk factor which is currently screened in selected populations is the Y-chromosome linked “gr/gr deletion”. With the recent advent of next-generation sequencing (NGS), the analysis of the entire exome has been successfully applied also to male infertility. Major advancements in discovering monogenic causes have been obtained in non-obstructive azoospermia and in monomorphic teratozoospermia. As a result of these discoveries, targeted gene panels that include genes with at least a moderate level of evidence for a gene–disease relationship are increasingly being implemented in clinical diagnostic settings.