Combination therapy targeting ribosome biogenesis (CX-5461: inhibits RNA Polymerase I transcription) and function (Everolimus: mRNA translation inhibitor targeting mTORC1 pathway) synergistically extend survival in a MYC-driven mouse model of lymphoma (Devlin et al., 2016, Cancer Discovery). However, despite the improved survival, the Eμ-MYC lymphoma-bearing mice eventually became resistant to this combination therapy and thus succumbed to disease. As both inhibitors target the cell’s most energy-demanding cellular activities, we hypothesize that the mechanism(s) of resistance involve coordinated changes in the cell’s translation and metabolic profiles. This study aims to investigate the resistance mechanisms and evaluate the potential of combining small molecules that modulate cellular metabolism with those that target the ribosome to improve the efficacy of the latter and sensitize the resistant cells. Our GC-MS-based metabolomics analysis showed that the combination therapy-resistant cells have upregulated metabolic activity compared to the single-agent resistant and naïve cells. We then employed poly(ribo)some profiling, a genome-wide analysis of the translatome, which revealed that the combination therapy-resistant cells had enhanced translation of mRNAs encoding components of the mitochondrial Complex I, as well as proteins associated with the cAMP signalling pathway. This suggests that these translation-driven metabolic reprogramming provided the basis for the reliance of the combination-therapy resistant cells to upregulated ATP production and activation of pro-survival mechanisms downstream of cAMP pathway. Our data, which integrated metabolomic and translatomic approaches to examine the functional basis of resistance, indicated the potential of combining inhibitors that target the ribosome with those that modulate cellular ATP and/or cAMP metabolism.