There is a male factor involved in up to half of all infertile couples. Potential etiologies in male factor infertility are many and require thorough evaluation for their accurate identification. A complete medical history in conjunction with a focused examination can allow for an appropriate choice of laboratory and imaging studies. The semen analysis is a crucial first step, but by no means is it sufficient to determine a specific etiology or dictate therapy. A systematic approach is necessary to help guide the work-up and rule out less likely causes. The etiologies discussed within this article are tremendously broad, and the prognosis for any given couple depends, in large part, on the etiology. Without a firm understanding of the genetics, anatomy, physiology, and complex interplay of the male reproductive system, the evaluation becomes an inefficient exercise that often fails to define the precise etiology. Couples with male factor infertility need a systematic approach with the efficiency of ultimate treatment determined largely by the physician's ability to identify the specific cause of the man's reproductive failure.