Multicellularity requires the organization of cells into specialized tissues. Cells that make up epithelial tissue are polarized; distinct outer (apical) and inner (basal) faces are central to their purpose. Previous studies in animal and cell culture model systems have revealed a number of polarity determinants that act coordinately to establish and maintain epithelial cell polarity under normal conditions. Recent work in Drosophila melanogaster has demonstrated that under starvation conditions, normal polarity signaling is not sufficient; activation of a distinct low-energy polarity pathway is required to maintain polarity. This low-energy polarity pathway is mediated by the LKB1-AMPK signaling module, which acts as a sensor of energy availability. Additional components of the pathway include dystroglycan and the growth regulator TOR, which are not required for epithelial cell polarity except under starvation conditions. Intriguingly, LKB1, AMPK1, dystroglycan, and TOR are all associated with incidence or progression of human epithelial cancers. These findings reveal important, yet unexplored connections between cell polarity, energy-dependent signaling, and cancer. A critical step in the investigation of these links is the identification of additional factors mediating both the low- and normal energy polarity pathways. Large-scale reverse genetic screening in Drosophila provides a powerful, new, and comprehensive approach to this problem. Recent advances in RNAi technology enhance and streamline the screening process, allowing for multiple targeted questions to be addressed. Accordingly, the aims are as follows: Aim 1: Identify novel factors involved in regulating epithelial cell polarity under low-energy conditions. Aim 2: Identify factors required for polarity under normal but not low-energy conditions.