Protein synthesis (mRNA translation) is a key step in regulation of gene expression and one of the most energy consuming processes in the cell. Energy metabolism and protein synthesis are dysregulated in a number of pathological states including cancer. However, how mRNA translation and energy production are coordinated remains incompletely understood. The mammalian/mechanistic target of rapamycin (mTOR) is a major pathway that regulates mRNA translation while dictating metabolic activity of cells. Our recent findings demonstrate that mTOR plays a pivotal role in coordinating protein synthesis and mitochondrial energy production via 4E-BP-dependent perturbations of the translatome. Moreover, we demonstrated that translational regulation is implicated in metabolic reprogramming of cancer cells, wherein it underpins metabolic plasticity of neoplasia. To this end, we showed that the mTORC1/4E-BP/eIF4E axis-dependent regulation of non-essential amino acid metabolism cooperates with HIF1alpha-directed modulations in glutamine metabolism to render cells less sensitive to combinations of clinically used kinase inhibitors and anti-diabetic biguanides. These findings suggest that although kinase inhibitors and biguanide combinations appear to be in general effective in targeting metabolic vulnerabilities of cancer cells, a subset of cancers may induce metabolic adaptations and resistance to these drug combinations via translational reprogramming. Conversely, we show that direct targeting of the eIF4F complex is effective in alleviating resistance to clinically used kinase inhibitors. Implications of these findings in improving the understanding of the molecular mechanisms underlying adaptation to energy stress and potential targeting of cancer-specific metabolic vulnerabilities will be discussed.