For well over 150 years, factors of safety (also known as safety factors) have been a fundamental engineering concept that expresses how much stronger a system is compared with the intended load. The pioneering work of Robert McNeill Alexander in the early 1980s applied this engineering concept to biomechanics. Over the next decade, evidence from comparative biomechanics supported the idea that safety factors are a fundamental principle of animal form and function. In terms of physiology, Jared Diamond related the maximal capacity of a physiological process to normal functional demands and incorporated evolutionary thinking into the concept of safety factors. It was proposed that evolutionary reasoning is required to understand the magnitudes of biological reserve capacities, an idea called ‘quantitative evolutionary design’. However, the general idea of safety factors as related to organismal form and function is much older. In 1906, Samuel James Meltzer, a physiologist and physician, presented the 5th Harvey Lecture to the New York Academy of Medicine; a lecture entitled ‘The Factors of Safety in Animal Structure and Animal Economy’, which was later published in Science in 1907. The 1907 paper is rarely cited and has never been cited within comparative biomechanics or comparative physiology. The purpose of this Commentary is to highlight Meltzer's historical contribution to the concept of safety factors as a general principle of organismal ‘design’.