Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is a critical intracellular pathway involved in cancer development. The PI3K pathway is dysregulated in various cancers, leading to increased cell proliferation, survival, and angiogenesis. Inhibition of PI3K signaling has emerged as a promising therapeutic strategy, with several drugs currently in clinical trials. These inhibitors are categorized into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-specific inhibitors. Despite their potential, PI3K inhibitors face challenges such as intrinsic and acquired resistance, which limit their efficacy. Resistance mechanisms include PI3K reactivation, activation of parallel pathways, and changes in the tumor microenvironment. Non-coding RNAs (ncRNAs) play a crucial role in regulating the PI3K pathway, and their dysregulation may contribute to drug resistance. Despite these challenges, isoform-selective PI3K inhibitors show promise in clinical trials for both solid and hematological malignancies. Identifying reliable biomarkers to guide patient selection and determine which tumor types benefit from PI3K inhibition remains an important area of research.Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is a critical intracellular pathway involved in cancer development. The PI3K pathway is dysregulated in various cancers, leading to increased cell proliferation, survival, and angiogenesis. Inhibition of PI3K signaling has emerged as a promising therapeutic strategy, with several drugs currently in clinical trials. These inhibitors are categorized into dual PI3K/mTOR inhibitors, pan-PI3K inhibitors, and isoform-specific inhibitors. Despite their potential, PI3K inhibitors face challenges such as intrinsic and acquired resistance, which limit their efficacy. Resistance mechanisms include PI3K reactivation, activation of parallel pathways, and changes in the tumor microenvironment. Non-coding RNAs (ncRNAs) play a crucial role in regulating the PI3K pathway, and their dysregulation may contribute to drug resistance. Despite these challenges, isoform-selective PI3K inhibitors show promise in clinical trials for both solid and hematological malignancies. Identifying reliable biomarkers to guide patient selection and determine which tumor types benefit from PI3K inhibition remains an important area of research.