This paper addresses theoretical challenges, still relevant today, that arose in the first decades of the twentieth century related to the concept of the organism. During this period, new insights into the plasticity and robustness of organisms as well as their complex interactions fueled calls, especially in the UK and in the German-speaking world, for grounding biological theory on the concept of the organism. This new organism-centered biology understood organisms as the most important explanatory and methodological unit in biological investigations. At least three theoretical strands can be distinguished in this movement: Organicism, dialectical materialism, and holistic biology. This paper shows that a major challenge of OCB was to describe the individual organism as a causally autonomous and discrete unit with consistent boundaries and, at the same time, as inextricably interwoven with its environment. In other words, OCB had to conciliate individualistic with anti-individualistic perspectives. This challenge was addressed by developing a concept of life that included functionalist and metabolic elements, as well as biochemical and physical ones. It allowed for specifying organisms as life forms that actively delimit themselves from the environment. Finally, this paper shows that the recent return to the concept of the organism, especially in the so-called “Extended Evolutionary Synthesis,” is challenged by similar anti-individualistic tendencies. However, in contrast to its early-twentieth-century forerunner, today’s organism-centered approaches have not yet offered a solution to this problem.