Trastuzumab-mediated cytotoxicity is mostly reversible. ErbB2 inhibition by trastuzumab reduces prosurvival signalings mediated by neuregulin-ErbB2-ErbB4 and is associated with a dramatic increase of proapoptotic Bcl-xS expression and a decrease of antiapoptotic Bcl-xL. This induces the opening of mPTP and generates ROS and mitochondrial dysfunctions among which loss of ΔΨ and ATP depletion with the disruption of cellular energetic, swollen mitochondria and reversibile contractile impairment. Cardiotoxicity of trastuzumab might also be related to its inhibition of AMPK which, in conditions of stress, leads to depletion of ATP stores. ErbB2/ErbB3 heterodimer controls Bcl-X and AMPK counteracting ATP depletion and destabilization of mitochondrial membrane, thus protecting contractile function. ErbB2 can translocate to the nucleus possibly acting on transcription and trastuzumab inhibition of ErbB2 has been suggested to regulate the expression of COX subunits.