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This chapter focuses on the genetic basis of male infertility. The male specific Y (MSY) is a chromosomal material that bridges the two polar pseudoautosomal regions and is unique in the human genome. A karyotype and Y-chromosomal microdeletion assay should be obtained as complementary tests in all non-obstructive azoospermia (NOA) and severely oligospermic men prior to intracytoplasmic sperm injection (ICSI) and the use of testicular sperm. Prognosis and planning are optimized with any informative result. Steroidogenic acute regulatory (StAR) protein is the rate-limiting step for androgen biosynthesis in particular and all steroids in general. The hypothalamic-pituitary-gonadal (HPG) axis controls human sexual maturation and spermatogenesis. The hypothalamus secretes gonadotropin- releasing hormone (GnRH) which regulates the production of Folliclestimulating hormone (FSH) and luteinizing hormone (LH) by the pituitary gonadotropes. Kallmann syndrome results from the failure of the GnRH-releasing neurons to migrate to the olfactory lobe during development.