Vitalism was long viewed as the most grotesque view in biological theory: appeals to a mysterious life-force, Romantic insistence on the autonomy of life, or worse, a metaphysics of an entirely living universe. In the early twentieth century, attempts were made to present a revised, lighter version that was not weighted down by revisionary metaphysics: “organicism”. And mainstream philosophers of science criticized Driesch and Bergson’s “neovitalism” as a too-strong ontological commitment to the existence of certain entities or “forces”, over and above the system of causal relations studied by mechanistic science, rejecting the weaker form, organicism, as well. But there has been some significant scholarly “push-back” against this orthodox attitude, notably pointing to the 18th-century Montpellier vitalists to show that there are different historical forms of vitalism, including how they relate to mainstream scientific practice (Wolfe and Normandin, eds. 2013). Additionally, some trends in recent biology that run counter to genetic reductionism and the informational model of the gene present themselves as organicist (Gilbert and Sarkar 2000, Moreno and Mossio 2015). Here, we examine some cases of vitalism in the twentieth century and today, not just as a historical form but as a significant metaphysical and scientific model. We argue for vitalism’s conceptual originality without either reducing it to mainstream models of science or presenting it as an alternate model of science, by focusing on historical forms of vitalism, logical empiricist critiques thereof and the impact of synthetic biology on current (re-)theorizing of vitalism.