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Organisms are central for biology. However, conceptualizing the unit of the organism is not easy. This Element discusses challenges to base biological reasoning and practice on the concept of organism. After many decades dominated by the paradigm of the gene, the organism is making a comeback in the bio- and biomedical sciences. It is again recognized as a causally efficacious, autonomous, and active unit that transcends the properties of genes and affects its own development and evolution – especially in fields like epigenetics, niche construction theory, and evolutionary developmental biology. This Element investigates these developments from a perspective of integrated history and philosophy of science. It focuses on conceptual, biotheoretical, and historical dimensions, as well as sociopolitical and anthropological aspects of today's 'return of the organism.' In particular, it discusses solutions for challenges of organism-centered biosciences in the 21st century. This title is also available as Open Access on Cambridge Core.