Spermatogenesis in the adult male depends upon the action of follicle stimulating hormone (FSH) and androgen. Ablation of either hormone has deleterious effects on Sertoli cell function and the progression of germ cells through spermatogenesis. In this study we have generated mice lacking both FSH receptors (FSHRKO) and androgen receptors on the Sertoli cell (SCARKO) to examine how FSH and androgen combine to regulate Sertoli cell function and spermatogenesis. Sertoli cell number in FSHRKO.SCARKO mice was reduced by about 50% but was not significantly different to FSHRKO mice. In contrast, total germ cell number in FSHRKO.SCARKO mice was reduced to 2% of control mice (and 20% of SCARKO mice) due to a failure to progress beyond early meiosis. Measurement of Sertoli cell-specific transcript levels showed that about a third were independent of hormonal action on the Sertoli cell while others were predominantly androgen-dependent or showed redundant control by FSH and androgen. Results show that FSH and androgen act through redundant, additive and synergystic regulation of spermatogenesis and Sertoli cell activity. In addition, the Sertoli cell retains a significant capacity for activity which is independent of direct hormonal regulation.