The PI3K/Akt/mTOR signaling pathway is crucial for cell growth and survival in both physiological and pathological conditions, including cancer. This pathway is highly interconnected and can be considered a single, unique pathway that interacts with many others, such as the hypoxia inducible factors (HIFs). The PI3K/Akt pathway is a key regulator of survival during cellular stress, and its role in cancer is significant due to the stressful environment of tumors. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates signals from nutrients, growth factors, and other cellular stimuli to regulate downstream signaling and protein synthesis. The activation of the PI3K/Akt/mTOR pathway leads to a profound disturbance of cell growth and survival, resulting in competitive growth advantage, metastatic competence, angiogenesis, and therapy resistance. This complex pathway has been considered one of the most attractive targets for the development of anticancer agents. The PI3K/Akt/mTOR pathway is targeted by various inhibitors, including mTOR inhibitors such as temsirolimus, everolimus, and ridaforolimus. These inhibitors work by forming a complex with the FK506 binding protein-12 (FKBP-12) and preventing mTOR activity, leading to inhibition of cell cycle progression, survival, and angiogenesis. Temsirolimus has been approved for the treatment of advanced renal cell carcinoma (RCC) and mantle cell lymphoma (MCL). Everolimus has been approved for the treatment of advanced RCC after failure of treatment with Sunitinib and/or Sorafenib, and for the treatment of progressive pancreatic neuroendocrine tumors (pNETs). Ridaforolimus has been evaluated in a phase III trial for the treatment of advanced sarcomas. PI3K and Akt inhibitors are still in early development stages, with no compounds reaching the bedside. However, several generations of PI3K inhibitors have been developed, including dual PI3K/mTOR inhibitors. These inhibitors target both PI3K and mTOR, potentially leading to stronger inhibition of the PI3K/Akt/mTOR pathway. Akt inhibitors are also being developed, but fewer have entered clinical development compared to PI3K inhibitors. Resistance to PI3K/Akt/mTOR inhibitors can occur through various mechanisms, including secondary target mutations, activation of alternative signaling pathways, and amplification of downstream alterations within the same pathway. The development of resistance is a major challenge in the treatment of cancer, and understanding the molecular basis of resistance is crucial for the development of more effective therapies. Despite the successes of mTOR inhibitors in various cancers, tumors ultimately evade inhibition of this pathway. Novel agents targeting PI3K/Akt/mTOR promise further improvement in treatment outcomes through higher selectivity and potency, as well as combinability with other therapeutic strategies. However, only translational research addressing the complex network of signaling pathways and mechanisms ofThe PI3K/Akt/mTOR signaling pathway is crucial for cell growth and survival in both physiological and pathological conditions, including cancer. This pathway is highly interconnected and can be considered a single, unique pathway that interacts with many others, such as the hypoxia inducible factors (HIFs). The PI3K/Akt pathway is a key regulator of survival during cellular stress, and its role in cancer is significant due to the stressful environment of tumors. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates signals from nutrients, growth factors, and other cellular stimuli to regulate downstream signaling and protein synthesis. The activation of the PI3K/Akt/mTOR pathway leads to a profound disturbance of cell growth and survival, resulting in competitive growth advantage, metastatic competence, angiogenesis, and therapy resistance. This complex pathway has been considered one of the most attractive targets for the development of anticancer agents. The PI3K/Akt/mTOR pathway is targeted by various inhibitors, including mTOR inhibitors such as temsirolimus, everolimus, and ridaforolimus. These inhibitors work by forming a complex with the FK506 binding protein-12 (FKBP-12) and preventing mTOR activity, leading to inhibition of cell cycle progression, survival, and angiogenesis. Temsirolimus has been approved for the treatment of advanced renal cell carcinoma (RCC) and mantle cell lymphoma (MCL). Everolimus has been approved for the treatment of advanced RCC after failure of treatment with Sunitinib and/or Sorafenib, and for the treatment of progressive pancreatic neuroendocrine tumors (pNETs). Ridaforolimus has been evaluated in a phase III trial for the treatment of advanced sarcomas. PI3K and Akt inhibitors are still in early development stages, with no compounds reaching the bedside. However, several generations of PI3K inhibitors have been developed, including dual PI3K/mTOR inhibitors. These inhibitors target both PI3K and mTOR, potentially leading to stronger inhibition of the PI3K/Akt/mTOR pathway. Akt inhibitors are also being developed, but fewer have entered clinical development compared to PI3K inhibitors. Resistance to PI3K/Akt/mTOR inhibitors can occur through various mechanisms, including secondary target mutations, activation of alternative signaling pathways, and amplification of downstream alterations within the same pathway. The development of resistance is a major challenge in the treatment of cancer, and understanding the molecular basis of resistance is crucial for the development of more effective therapies. Despite the successes of mTOR inhibitors in various cancers, tumors ultimately evade inhibition of this pathway. Novel agents targeting PI3K/Akt/mTOR promise further improvement in treatment outcomes through higher selectivity and potency, as well as combinability with other therapeutic strategies. However, only translational research addressing the complex network of signaling pathways and mechanisms of