Unexplained infertility is a common diagnosis among couples with infertility. Pragmatic treatment options in these couples are directed at trying to improve chances to conceive, and consequently intrauterine insemination (IUI) with ovarian stimulation and in vitro fertilization (IVF) are standard clinical practice, while expectant management remains an important alternative. While evidence on IVF or IUI with ovarian stimulation versus expectant management was inconclusive, these interventions seem more effective in couples with a poor prognosis of natural conception. Strategies such as strict cancellation criteria and single-embryo transfer aim to reduce multiple pregnancies without compromising cumulative live birth. We propose a prognosis-based approach to manage couples with unexplained infertility so as to expose less couples to unnecessary interventions and less mothers and children to the potential adverse effects of ovarian stimulation or laboratory procedures.