Wee kinases control mitotic entry by catalyzing inhibitory phosphorylation of the eukaryotic mitotic regulatory kinase, Cdk1. This mechanism prevents mitosis from initiating during S phase and delays mitosis by prolonging G2 in response to DNA damage and developmental signals. Like other metazoans, Drosophila has two Wee1-like kinases: a nuclear protein (Wee1) and a cytoplasmic protein (Myt1), both of which we have cloned and are characterizing during development, using genetic and molecular approaches. We showed previously that Wee1 has a unique and essential function during the cleavage stage of embryogenesis, without which embryos undergo lethal mitotic catastrophe during the late syncytial divisions. This function does not apparently depend on the known biochemical function for Wee1 (phosphoinhibition of Cdk1) and experiments to determine the relevant mechanism will be discussed. Over-expression of Dwee1 and Dmyt1 during the second mitotic wave of eye development causes defective ommatidia to form. These over-expression phenotypes can be modified by altering the genomic dosage of known regulators of the G2/M transition, suggesting that we can use a genetic modifier approach to screen for cell cycle regulators that have not previously been identified. A genome-wide screen of deletions encompassing 70-80% of the Drosophila genome has identified a number of loci as enhancers or suppressors of the ectopic Wee1 or Myt1 eye phenotypes. These loci are good candidates for regulators of Wee kinases that couple developmental events with mitotic controls. Another interesting interaction we have seen is between the two Wee kinases and p53, a metazoan tumor suppressor gene that is mutated in a majority of human cancers. p53-induced apoptosis during eye development is strikingly suppressed by co-expression of either Wee1 or Myt1, an effect that is consistent with previously proposed roles for Cdk1 activity in promoting certain aspects of apoptosis. We will discuss our progress in assessing the physiological significance of these observations.