Clinical development for orphan drugs is extremely demanding but fascinating. There is no single aspect that is really specific to it but instead it gathers most of the hurdles: design, outcomes, recruitment, ethics, cost, probability and predictability for success. To overcome these difficulties, there has to be a great collaboration between academic centers, small and large pharma companies, patients’ representatives as well as health authorities to provide support and innovative approaches. The ultimate goal is to give access to patients with unmet medical needs to drugs with a favorable benefit-risk ratio. We review and discuss here the pillars for a successful clinical development for orphan drugs.