The steroid hormone ecdysone regulates the major post-embryonic transitions during the Drosophila life cycle, including the onset of, and progression through, metamorphosis. Reviewed here are several recent studies that together give insight into both the transduction of the ecdysone signal itself as well as other possible hormonal signaling events associated with metamorphosis. Genetic studies of the two components of the ecdysone receptor, EcR and usp, demonstrate that they are essential for the initiation of metamorphosis in Drosophila. These genes are not, however, required for some earlier events that prepare the animal for metamorphosis. Instead, the orphan nuclear receptor DHR78 appears to regulate these events, possibly in response to an as yet unidentified hormone. An additional role for usp, independent from EcR function, has also been uncovered in epidermis and cuticle development, suggesting a possible role for usp in integrating ecdysone and juvenile hormone signals.