Hedgehog (HH) signaling regulates a diversity of processes involved in developmental patterning, stem cell growth and maintenance, and cancer etiology. Despite its biological importance, the HH signal transduction pathway remains largely mysterious. Our past understanding of the HH pathway signaling components and mechanisms came from groundbreaking genetic and biochemical studies in the fruit fly Drosophila melanogaster. Some of these mechanisms are strikingly conserved in vertebrates, although some specific aspects are clearly divergent. In this article, we discuss recent findings for cross talk in HH signal transduction with PI3K signaling through Akt, and with PKC-δ signaling through MEK-1, indicating that these pathways converge to control the Gli transcription factor. The integration of these convergent pathways on the regulation of mammalian Sonic Hedgehog signaling highlights their potential involvement in the control of HH-dependent events in development and tumorigenesis.