Cryptorchidism is the most frequent congenital birth defect in male children (2–4% in full-term male births) and it has the potential to impact the health of the human male. In fact, although it is often considered a mild malformation, it represents the best characterized risk factor for reduced fertility and testicular cancer. Furthermore, some reports have highlighted a significant increase in the prevalence of cryptorchidism over the last few decades. Etiology of cryptorchidism remains for the most part unknown, and cryptorchidism itself might be considered a complex disease. Major regulators of testicular descent from intra-abdominal location into the bottom of the scrotum are the Leydig-cell derived hormones testosterone and Insulin-like factor 3 (INSL3). Research on possible genetic causes of cryptorchidism has increased recently. Numerous animal evidence supports a genetic cause, whereas the genetic contribution to human cryptorchidism is being elucidating only recently. Mutations in the gene for INSL3 and its receptor and in the androgen receptor gene have been recognized as causes of cryptorchidism in some cases, but also some chromosomal alterations, above all the Klinefelter syndrome, are frequently involved. Environmental factors acting as endocrine disruptors of testicular descent might also contribute to the etiology of cryptorchidism and its increased incidence in last years. Furthermore, polymorphisms in different genes have recently been investigated as contributing risk factor for cryptorchidism, alone or by influencing susceptibility to endocrine disruptors. Obviously, the interaction of environmental and genetic factors is fundamental and many aspects are being clarifying only recently.