The phosphoinositide 3'-kinase (PI3K)/Akt signaling cascade controls cellular processes such as apoptosis and proliferation. Moreover, it is a mediator of insulin effects on target cells and as such is a major regulator of fuel metabolism. The PI3K/Akt cascade was demonstrated to be activated by stressful stimuli, including heat shock and reactive oxygen species (ROS). This minireview focuses on activation of the pathway by exposure of cells to heavy metal ions, Cu2+ and Zn2+. It is hypothesized that stimulation of PI3K/Akt is the molecular mechanism underlying the known insulin-mimetic effects of copper and zinc ions. Following a brief summary of PI3K/Akt signaling and of activation of the cascade by Cu2+ and Zn2+, mechanisms of metal-induced PI3K/Akt activation are discussed with a focus on the role of ROS and of cellular thiols (glutathione, thioredoxin) and protein tyrosine phosphatases in Cu2+ and Zn2+ signaling. Finally, consequences of metal-induced PI3K/Akt activation are discussed, focusing on the modulation of FoxO-family transcription factors by Cu2+ and Zn2+.