The phosphatidylinositol 3 kinase(PI3K) pathway is frequently altered in cancer, including ovarian cancer(OC). Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin(m TOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective m TOR complex-1(m TORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual m TORC1/m TORC2, Akt, and PI3 K inhibitors. Although it is likely that inhibition of the PI3K/Akt/m TOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha(PIK3CA) and/or phosphatase and tensin homolog(PTEN) alterations, may be particularly suited to this approach. Given the complexity and redundancy of the PI3 K signaling network, PI3 K pathway inhibition may be most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in appropriately selected OC patients. Here, we discuss the relevance of the PI3 K pathway in OC and provide an up-to-date review of clinical trials of novel PI3 K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed. Unfortunately, despite a sound biological rationale and encouraging activity in preclinical models, trials of first-generation inhibitors of mammalian target of rapamycin (m TOR) in OC have demonstrated negative results. The lack of patient selection as well as resistance to selective m TOR complex-1 (m TORC1) inhibitors could explain the disappointing results thus far. Nonetheless, a number of novel agents are being investigated, including dual m TORC1 / m TORC2, Akt, and PI3 K inhibitors. Although it is likely that inhibition of the PI3K / Akt / m TOR pathway may have little effect in unselected OC patients, certain histological types, such as clear cell or endometrioid OC with frequent phosphatidylinositol -4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and / or phosphatase and tensin homolog (PTEN) alterations, may be particularly suited to this approach. Given the complexi ty and redundancy of the PI3 K signaling network, PI3 K pathway inhibition may be the most useful in combination with either chemotherapy or other targeted therapies, such as MEK inhibitors, anti-angiogenic therapy, and hormonal therapy, in selected OC patients. Here, we discuss the relevance of the PI3 K pathway in OC and provide an up-to-date review of clinical trials of novel PI3 K inhibitors alone or in combination with cytotoxics and novel therapies in OC. In addition, the challenges of drug resistance and predictive biomarkers are addressed.