Fifteen years ago in October, PLOS Medicine was launched with the intent to reinvent the medical journal. Our mission to serve as the leading open-access medical journal is unchanged and remains, we believe, as pressing and essential now as it was at launch. In this Editorial we highlight priorities for the journal in meeting the needs and expectations of clinicians and researchers in the coming years. We also reflect on the evolution of some of the major medical and health challenges affecting the world’s people since our tenth anniversary [1] and discuss some recognizable changes in thinking and approaches in health research, clinical practice and medical publishing. We are also taking this opportunity, along with selected members of our Editorial Board, to highlight our favorite research and commentary articles in a series of blog posts at Speaking of Medicine (https://blogs.plos.org/speakingofmedicine/).

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