Generation of three-dimensional tissues with distinct cell types is required for the development of all organs. On its own, mitotic spindle orientation allows tissues to change in length or shape. In combination with intrinsic or extrinsic cues, this can also be coupled to the generation of diverse cell fates-a process known as asymmetric cell division (ACD). Understanding ACDs has been greatly aided by studies in invertebrate model systems, where genetics and live imaging have provided the basis for much of what we know. ACDs also drive the development and differentiation of the epidermis in mammals. While similar to the invertebrate models, the epidermis is distinct in balancing symmetric and asymmetric divisions to yield a tissue of the correct surface area and thickness. Here, we review the roles of spindle orientation in driving both morphogenesis and cell fate decisions. We highlight the epidermis as a unique model system to study not only basic mechanisms of ACD but also their regulation during development.