The tumor suppressor PTEN was originally identified as a negative regulator of the phosphoinositide 3-kinase (PI3K) signaling, a main regulator of cell growth, metabolism and survival. Yet this function of PTEN is extremely relevant for its tumor-suppressive ability, albeit the recent characterization of many PI3K-independent tumor-suppressive activities. PI3K-mediated PIP(3) production leads to the activation of the canonical AKT-mTORC1 pathway. The implications of this signaling cascade in health and disease have been underscored by the high number of regulators within the pathway whose alterations give rise to different malignancies, including familiar syndromes, metabolic dysfunctions and cancer. Moreover, PI3K is tightly buffered at multiple levels by downstream components, which have turned this signaling pathway literally upside down. PI3K and its downstream components in turn cross-talk with a number of other pathways, thereby leading to a complex network of signals that may have dramatic consequences when perturbed. Here, we review the current status of the PTEN-PI3K signaling pathway with special emphasis on the most recent data on targets and regulation of the PTEN-PI3K axis. This provides novel provocative therapeutic implications based on the targeted modulation of PI3K-cross-talking signals.