The adult adrenal medulla contains precursor cells thought to contribute to the gland’s plasticity. The presence of these stem cells provides an extraordinary model to study the process of stem cell activation, the passage from quiescence to proliferation. This is not only of direct relevance to stress adaptation but also to tumourigenesis. We propose a multi-disciplinary approach to study mechanisms underlying adrenomedullary stress adaptation and development of neoplasia by utilizing in vivo and in vitro models of adult adrenal medulla stem cell activation. We will compare the induced cellular changes with genomic and proteomic databases from human adrenal neoplasms, which represent a “super-activated” paradigm. The in vivo activation will involve established stress models using transgenic nestin-GFP reporter mice, where the precursor cell labelling was already validated. In vitro, we will use cultures from bovine and mouse adrenals to test treatments that we predict will increase survival and proliferation. Treatments are chosen based on a signal transduction pathway shown to regulate the expansion of stem cells from various sources. Additional treatments will be tested following consultation from the tumour databases. Besides improving our understanding of adreno-medullary adaptation to stress and tumourigenesis, the here proposed studies may prove the adrenal medulla as a superb model system to identify new mechanisms likely to translate to other tissues.