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The coincidence of anniversaries associated with the publication of William Russell and Rex Burch’s The Principles of Humane Experimental Technique, the founding of the Fund for the Replacement of Animals in Medical Experiments (FRAME), and the establishment of the collaboration between FRAME and the University of Nottingham, provides an opportunity to reflect on Russell and Burch’s legacy and how it was carried forward by FRAME. The Principles, published in 1959, was the pioneering work in what later became the alternatives or Three Rs field of replacement, reduction, and refinement of animal use. Such was the book’s initial and undeserved obscurity, however, that FRAME, following its founding in 1969, pioneered a similar approach independently of Russell and Burch’s work. The Humane Society of the United States (HSUS) was also an early champion of the alternatives framework, and through the establishment of the Russell and Burch Award, helped unite Russell and Burch with what had emerged as the alternatives community. Thanks largely to FRAME, Russell and Burch were able to participate in Three Rs activity before their deaths. They lived long enough to see their ideas take hold, but not long enough to see the emerging revolution currently under way in toxicity testing, toward the use of non-animal methods.