The PI3K/AKT/mTOR pathway is a critical intracellular signaling pathway involved in cancer development and progression. This review summarizes the role of the PI3K pathway in tumor development, recent developments in PI3K inhibitors based on clinical trials, and the mechanisms of resistance to PI3K inhibition. PI3K inhibitors are classified into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-specific inhibitors. These inhibitors have shown promise in clinical trials for various cancers, but intrinsic and acquired resistance remains a challenge. Resistance mechanisms include PI3K reactivation, activation of parallel pathways, and tumor microenvironment changes. The review also discusses the role of non-coding RNAs in regulating PI3K signaling and their potential involvement in resistance. Current clinical trials are evaluating the efficacy and safety of various PI3K inhibitors, including dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-specific inhibitors, in different cancer types. Despite the challenges, ongoing research aims to improve the therapeutic efficacy of PI3K inhibitors through combination therapies and alternative approaches.The PI3K/AKT/mTOR pathway is a critical intracellular signaling pathway involved in cancer development and progression. This review summarizes the role of the PI3K pathway in tumor development, recent developments in PI3K inhibitors based on clinical trials, and the mechanisms of resistance to PI3K inhibition. PI3K inhibitors are classified into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-specific inhibitors. These inhibitors have shown promise in clinical trials for various cancers, but intrinsic and acquired resistance remains a challenge. Resistance mechanisms include PI3K reactivation, activation of parallel pathways, and tumor microenvironment changes. The review also discusses the role of non-coding RNAs in regulating PI3K signaling and their potential involvement in resistance. Current clinical trials are evaluating the efficacy and safety of various PI3K inhibitors, including dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-specific inhibitors, in different cancer types. Despite the challenges, ongoing research aims to improve the therapeutic efficacy of PI3K inhibitors through combination therapies and alternative approaches.