In recent years pharmaceutical companies have implemented Operational Excellence (OpEx) in their R&D organizations to improve productivity but had only limited success. Practitioners and management start to question the effectiveness of process-focused improvement methodologies. In this article, we illustrate a number of challenges OpEx practitioners face and argue that our long-held assumptions and lack of understanding of pharmaceutical R&D can prevent us from seeing the real problems. We recommend a balanced approach by integrating process management with organization’s project management capability in order to better engage the stakeholders and deliver both short-term results and long-term improvement.