Male infertility is a multifactorial complex disease with highly heterogeneous phenotypic representation and in at least 15% of cases, this condition is related to known genetic disorders, including both chromosomal and single-gene alterations. In about 40% of primary testicular failure, the etiology remains unknown and a portion of them is likely to be caused by not yet identified genetic anomalies. During the last 10 years, the search for ‘hidden’ genetic factors was largely unsuccessful in identifying recurrent genetic factors with potential clinical application. The armamentarium of diagnostic tests has been implemented only by the screening for Y chromosome-linked gr/gr deletion in those populations for which consistent data with risk estimate are available. On the other hand, it is clearly demonstrated by both single nucleotide polymorphisms and comparative genomic hybridization arrays, that there is a rare variant burden (especially relevant concerning deletions) in men with impaired spermatogenesis. In the era of next generation sequencing (NGS), we expect to expand our diagnostic skills, since mutations in several hundred genes can potentially lead to infertility and each of them is likely responsible for only a small fraction of cases. In this regard, system biology, which allows revealing possible gene interactions and common biological pathways, will provide an informative tool for NGS data interpretation. Although these novel approaches will certainly help in discovering ‘hidden’ genetic factors, a more comprehensive picture of the etiopathogenesis of idiopathic male infertility will only be achieved by a parallel investigation of the complex world of gene environmental interaction and epigenetics.