There are numerous cell signalling pathways that exhibit cross-talk with the PI3K pathway, potentially allowing cancer cells to escape inhibition of PI3K. As such, inhibition of the PI3K pathway alongside other targets could offer a synergistic response, such as that seen with PI3K and MEK co-targeted inhibition in lung cancer cells. More recently, co-targeting the PI3K pathway with PIM kinases has been suggested, with numerous pre-clinical studies suggesting the potential benefit of this approach. Development of panels of cell lines that are resistant to inhibition of the PI3K pathway may lead to the identification of future co-targets, and better understanding of which pathways may compensate for loss of PI3K signalling following drug treatment. Combined PI3K inhibition with more traditional therapies such as chemotherapy may also offer improved response over inhibition of PI3K alone.