Payments for Ecosystem Services (PES) mechanisms leverage economic and social incentives to shape how people influence natural processes and achieve conservation and sustainability goals. Beneficiaries of nature's goods and services pay owners or stewards of ecosystems that produce those services, with payments contingent on service provision. Integrating scientific knowledge and methods into PES is critical. Yet many projects are based on weak scientific foundations, and effectiveness is rarely evaluated with the rigor necessary for scaling up and understanding the importance of these approaches as policy instruments and conservation tools. Part of the problem is the lack of simple, yet rigorous, scientific principles and guidelines to accommodate PES design and guide research and analyses that foster evaluations of effectiveness. As scientists and practitioners from government, nongovernment, academic, and finance institutions, we propose a set of such guidelines and principles.