Different chemicals are known to cause testicular damage in the human male and experimental animals. However, the ability to assess the potential and mechanism of action leading to chemically-induced damage in men has been hampered by a lack of good predictive models. Although many of these chemicals were found to impair reproductive capacity in various laboratory animals, only some have caused reproductive damage in men. Mammalian spermatogenesis takes place within the avascular seminiferous tubules of the testis. Specialized tight junctions, which form between adjacent Sertoli cells at the time of puberty, divide the tubular space into the basal and adluminal compartments, and create a “blood-testis” barrier that restricts passage of substances and ions from the circulation. Thus, the completion of meiosis and post-meiotic germ cell differentiation, which take place in the adluminal compartment, are isolated from circulating substances unable to cross the blood-testis barrier. It seems feasible, therefore, that damage to the germ cells induced by testicular toxicants may be mediated through other cells in the testis such as the Sertoli, peritubular, or Leydig cells. A recently developed two-compartment system for culture of testicular cells can simulate, to some degree, the normal physiologic conditions. In principle, Sertoli cells isolated from mammalian testes are cultured on a permeable support (that is millipore filter) between two fluid compartments. They form a highly polarized epithelial layer with characteristics tight junctions that restrict the passage of substances between the two compartments, in analogy to the blood-testis barrier. We believe this system provides an excellent in vitro model for determining the ability of chemicals to: a) alter the permeability of the blood-testis barrier, b) impair the secretory function of Sertoli cells, or c) affect their viability, all of which could indirectly affect the germ cells. We have utilized this system for examining the effects of cadmium chloride (CdCl2) and other toxic substances known to affect the testis. The Leydig cell toxicity was investigated in testicular perfusion system or cultures of isolated Leydig cells.