Tumor genetic analyses have revealed that the signaling pathways regulated by PI3K and RAS are of fundamental importance in a wide variety of human neoplasms, leading to intensive efforts to develop therapeutics that block signaling through these two key pathways. Both pathways frequently undergo a variety of activating alterations, including oncogenic mutations, amplification events and loss of tumor-suppressor genes that are thought to confer aggressive growth properties and enhance survival on neoplastic cells. An attractive hypothesis is that these alterations provide an indication that a particular tumor is addicted to signaling through the affected pathway, thus may provide ideal candidate predictive biomarkers to target these inhibitors to appropriate patient populations. This review highlights recent preclinical progress made on understanding the predictive value of key pathway alterations in response to targeted therapeutics directed against PI3K, AKT, mTOR, BRAF and MEK, and the prospects for biomarker-driven clinical strategies for such inhibitors.