Objective: Innovation evokes different concepts across stakeholders in the lifecycle of medicines; each with consequent approaches to foster it. We aim at reviewing and comparing definitions, incentives and rewards to innovation among decision-making agents in the US and Europe (EU, Austria, Belgium, France, Germany, Italy, Netherlands, Sweden and UK). Methods: Review of the specialized literature through Medline and grey sources (guidelines, legislation and official communications, and decisions) illustrated with a case study in oncology. Results: Definition of innovation varies significantly across stakeholders. The establishment of a New Chemical Entity by patenting an invention is followed by the registration of a pharmaceutical product that may or may not get assigned a new ATC class. Then, regulators assess the degree of innovation more comprehensively to consider early access (FDA, EMA). Finally, HTA bodies measure the value of that innovation in terms of patient, caregiver and/or societal benefit in order to determine premium pricing and coverage. Criteria for differentiation varies across countries (formulation, mechanism of action, mode of administration, etc.). Premium pricing for a patent-protected innovative product requires therapeutic advantage in terms of safety, efficacy (HAS), quality (IQWIG-GBA), morbidity and quality of life (CRM), or cost (VO-EKO, TLV and NICE) and demonstrated additional clinical benefit over existing therapies. Other criteria such as unmet need or disease severity have been considered though rarely and the value of incremental innovation or patients/carers’ convenience have been insufficient to justify premium pricing by themselves. Conclusion: Patent protection, marketing authorization and pricing/reimbursement systems serve different purposes so the thresholds to define “innovativeness” escalate with each step and so do geographical disparities. IP protection follows international conventions. Incentives for innovation are rather consistent across regulators; entailing mainly expedite procedures and less burdensome evidence generation demands. Conversely, priorities for pricing/reimbursement to recognize and reward innovation do not always align.