Big Pharma's blockbuster model-which entails developing new drugs for diseases affecting a very large number of patients, promoting it to physicians as the new best-in-class treatment, and profiting from the ensuing volume of sales-is under threat. In the last 2 decades, the largest pharmaceutical firms have lost billions of dollars in shareholder value, due to a combination of factors such as declining R&D productivity, stricter regulatory requirements, more intense generic competition, and an increasingly ineffective marketing model. I review societal, demographic, regulatory, and technological trends and discuss how such trends are contributing to the rise of a new class of empowered patients. I discuss the implications of patient empowerment for the patient-physician relationship and for therapy launch and therapy promotion. Building on real-world evidence, I discuss the benefits and challenges of direct-to-patient marketing strategies such as nurturing partnerships with key patient opinion leaders and direct-to-patient communication via social media. Through a content analysis of the 2005-2010 annual reports of the largest 20 pharmaceutical firms, I show that, despite strict regulatory requirements, several firms have started to embrace patient empowerment as a key component of their marketing models. However, much remains to be done. I propose that now is the right time for pharmaceutical marketers (and scholars) to implement marketing strategies that help empowering patients. In addition, I also discuss the importance of avoiding that patient empowerment results in healthcare consumerism, which could have destructive consequences for patient-physician (and firm-physician) relationships.