Long-term declines in the productivity of pharmaceutical R&D threaten the sustainability of the current business model. A major driver of the decline has been the rising cost, and increased rate of failure, of projects across the industry, caused in part by the confluence of new approaches, novel technologies, higher go/no-go hurdles and organizational challenges. Here we examine several of the top culprits that are charged with driving this decline and the merits of the cases against them, and speculate on the emerging trends that will underpin the industry's future productivity.