Investigation of α-cells has long been constrained by their scarce population and localization at the islet mantle which exposes α-cells to injury by conventional islet isolation and dispersion to single cells that employ damaging enzymatic and mechanical means. To surmount these limitations, we recently reported employing the pancreas slice preparation which enables highly efficient acute in situ electrophysiological (patch clamp) examination of α-cells within its unperturbed native social environment with preserved paracrine regulation. In this review, we compare the electrophysiological properties of α-cells in these three preparations, and discuss the current view of glucose regulation of α-cells. We discuss current genetic mouse models that flurophore-tagged α-cells (GYY) and β-cells (MIP-GFP) which can reliably identify islet cells to facilitate their study. Combining these strategies should enable future studies directed at the precise assessment of the perturbation in intrinsic and paracrine regulation of α-cells contributing to abnormal glucose homeostasis in diabetes.