- The dilemma of unexplained infertility posed by Southam in 1960 remains today: despite advances in the diagnostic assessment of infertility, many couples still have no explanation for their infertility. Even the most sophisticated evaluation of semen, ovulation and genital tract competence cannot reveal all of the possible defects in the complex process leading to conception. Because it arises from these shortcomings in our knowledge of fertilization and from our inability to utilize all of the current knowledge, unexplained infertility is a challenge for both biological and clinical research. This paper attempts to summarize some clinical issues in the management of unexplained infertility: the prevalence of the disorder, problems in the definition and possible explanations for the existence of this diagnostic category. It reviews outcome-based clinical publications as a guide to decision-making on what diagnostic tests to use, provides a summary of the untreated prognosis and evaluates study results that may serve as a basis for treatment decisions in this puzzling diagnostic category of infertility.