A manned mission to Mars and the establishment of the first human settlement in outer space was once a mere figment of science fiction but is now being planned and expected to take place in the following twenty years. Mars is under consideration as the next planet beyond Earth to support continuous human exploration. Unfortunately, such an endeavor comes with titanic challenges in various disciplines, from space travel technology to medical, biological, social and ethical challenges. Reproduction involves many aspects of human life, and is also the subject of various disciplines. We assume that human reproduction in a Mars settlement will be necessary for the long-term success of an outer space mission. Thus, here we explore and discuss the challenges involving the likely scenario of human reproduction in Mars. To anticipate the many issues associated with human reproduction outside Earth, we applied multidisciplinary approaches to discuss possible social, ethical, medical and biological challenges of human reproduction on Mars.