The PI3K/Akt signalling pathway and its downstream transcription factors have been intensively studied for their role in cell proliferation, survival, cycle control, as well as other cellular functions. There is growing evidence showing that dysregulation of this pathway also plays an essential role in cancer development. The overexpression or permanent activation of RTKs and GPCRs, as well as the exposure to environmental carcinogens cause constant activation of PI3K/Akt. On the other hand, PI3K/Akt themselves can also become hyperactivated due to gene amplification or PTEN inactivation. Consequently, the targets downstream of PI3K/Akt can be abnormally activated, which promote proliferation and survival of cancer cells in carcinogenesis. Among these targets we find that the NFkappaB and AP-1 are the most interesting. Therefore, methods and compounds aiming to inhibit the altered components of this pathway can simultaneously prevent the proliferation of tumor cells and sensitize them toward apoptosis. To this regard, the natural compounds from vegetables and fruits with high affinity and non toxicity to target the PI3K/Akt pathway and prevent cancer are attractive.