To summarize the current understanding of the global burden of musculoskeletal pain-related conditions, consider the process of evidence generation and the steps to generate global pain estimates, identify key gaps in our understanding, and propose an agenda to address these gaps, we performed a narrative review. In the 2010 Global Burden of Disease Study (GBD), which broadened the scope of musculoskeletal conditions that were included over previous rounds, low back pain imposed the highest disability burden of all specific conditions assessed, and subsequent GBD reports further reinforce the size of this burden. Over the past decade, the GBD has produced compelling evidence of the leading contribution of musculoskeletal pain conditions to the global burden of disability, but this has not translated into global health policy initiatives. However, system- and service-level responses to the disease burden persist across high-, middle-, and low-income settings. There is a mismatch between the burden of musculoskeletal pain conditions and appropriate health policy response and planning internationally that can be addressed with an integrated research and policy agenda.