Walter Elsasser (1904-1991), an eminent quantum physicist and geophysicist, was also active in theoretical biology over a 35-year period from the early 1950s to the late 1980s. Although increasingly estranged from the biological establishment during the last fifteen years of his life, Elsasser’s central concern with complexity has resulted in a revival of interest in his theories over the last decade, particularly among those who see biology from a systems holist rather than a molecular reductionist viewpoint. This article reviews the development of Elsasser’s thought from his early opposition to genetic determinism, through the radical epistemology of his middle period, to his later more broadly philosophical ideas. After a summary of existing responses to Elsasser in the literature, a fresh critique and assessment of his work is presented, with particular attention to the implications for systems biology. It is concluded that although Elsasser drew some conclusions from his epistemology that are not justifiable in the light of subsequent research, his insistence on the existence of biotonic phenomena in biology, irreducible (either at present, or in principle) to physics, is correct. Ironically, the most significant biotonic principle is one which Elsasser largely ignored in his own work, that of Natural Selection.