Orphan diseases pose both a challenge to the global medical community and an opportunity for it to focus on global peace engineering and innovation. Where, any single orphan disease is rare, when taken as a whole they affect more than 250 million people throughout the world. This number by comparison is larger than the global number of cancer and AIDS patients. We add to the literature by mapping the available knowledge in the orphan drug development field and exploring the tensions at play for innovation and entrepreneurship in this field. We further add to the literature by providing a framework to review this field based on social systems theory. Our review highlights the gaps in research and proposes a path forward in understanding of and learning from the orphan drug development field.