Stem cells have a central place in biology. Through their ability to self-renew and differentiate, they maintain, repair and, in some cases, regenerate tissues. However, there is no consensus nowadays on what exactly is a stem cell. Experimental data accumulated in recent years have challenged the traditional view that stem cells are discrete and isolable entities and that differentiation is an irreversible process. They also revealed an unsuspected heterogeneity between different varieties of stem cells. This context of conceptual questioning is conducive to philosophical analysis, and several contributions from philosophers have already led to important clarifications, particularly on the properties of self-renewal and differentiation, or on conflicting conceptions of stem cells. But the work of stem cell philosophers constantly faces limitations due to lack of appropriate data. Based on this observation, our STEM project combines philosophy with phylogenetic and experimental approaches, which together will lead to a better understanding of stem cells. In an earlier analysis of stem cell diversity, we have showed that stemness could be four types of property, each having a different ontology. Depending on the tissue, it may be a categorical property (intrinsic), a dispositional property (intrinsic but whose expression depends on extrinsic stimuli), a relational property (extrinsic, induced by the microenvironment), or a systemic property (extrinsic, regulated at the level of the cell population). This analysis raised two issues that are the subject of STEM. (1) Stem cell unity: If stemness can be of different natures, does it mean that the stem cell category artificially regroups different cell types? In other words, are stem cells a natural kind? (2) Stability of stemness ontology: Are the four stemness ontologies mutually exclusive or porous? That is to say, is the nature of stemness stable for each stem cell variety or can it switch from being one type of property to being another in certain contexts such as regeneration or pathology? Both of these issues have important implications for biology and medicine as answers to these questions lead to different research programs and therapeutic strategies. To resolve the question of stem cell unity, we will use a phylogenetic approach to determine whether stem cells have a common evolutionary origin or whether our classification describes stem cell types with separate origins—in the latter case stem cells cannot belong to a natural kind. To study the stability of stemness, we will use experimental approaches to explore stemness in a regenerative context (with an animal model with high regenerative capacity) and in a pathological context (with a murine model of acute myeloid leukemia induced by a translocation that allows the acquisition of stemness by non-stem cells). We will examine implications of these data for stem cell biology and clinical applications. Experimental and phylogenetic analyses will also allow us to renew the work undertaken by other philosophers that faced limitations of available data, particularly the proposal to develop a definition of stem cells by homeostatic property cluster that holds great promise but failed to efficiently distinguish stem cells from non-stem cells. Finally, we will adopt a larger perspective on the methodology used in this project and analyze the benefits, risks and pitfalls of the integration of scientific approaches for philosophical purposes.