Purpose – The purpose of this paper is to examine value creation pathways in biopharma innovation ecosystems (IEs) by establishing a theoretical model and providing insights into the Lombardy case.Methodology – A two-step research strategy has been adopted. First, a panel study of the top IE stakeholder representatives was organized through semistructured interviews. Concurrently, a quantitative phase was carried out by collecting data to recognize the value creation pathways within the Lombardy biopharma IE.Findings – The major paper findings lie in the developed theoretical IE model and its application to the Lombardy case, which provides a common basis of analysis for different biopharma IEs, e.g., Boston-Cambridge, San Francisco Bay area, Cambridge UK. The final thesis of the paper advocates the idea that although the Boston-Cambridge economic and technical figures show an IE that is extraordinarily different from the Lombardy IE, the latter has evolved based on its inherent limits and strengths and succeeded in deploying remarkable value creation pathways toward niche-biopharma markets and health and med-tech markets.Value – This paper represents one of the first attempts to systematically and longitudinally analyze biopharma IE from a holistic perspective. The holistic and systemic framework developed in the paper can help to understand the potential of the IE approach for the biopharmaceutical industry. In this context, it is notable that multiplayer concurrent engagement through specific comparative advantages is an essential requirement for pursuing cutting-edge innovation within the biopharma industry.