Nonobstructive azoospermia (NOA) has remained a clinical and scientific dilemma in the field of male infertility, yet perhaps no population remains as challenging to manage as those who have failed initial treatment. Although modern surgical techniques have provided hope to men who have in the past been deemed sterile, there is no current consensus on the management of those who have failed their initial sperm retrieval procedure. Despite these obstacles, men with NOA (even those with a failed primary therapy) have the potential to father biologic progeny. It is therefore the goal of this chapter to synthesize the most current options available to the reproductive physician—including preoperative optimization, surgical management, and emerging technologies—allowing for optimal care of the most difficult patient population in all of male infertility.