Despite the success of therapies targeting oncogenes in melanoma, clinical outcomes are limited by a residual disease that results in relapse. This residual disease is characterized by drug-induced adaptation, however the underlying mechanisms that control this adaptive cellular plasticity are largely unknown. We have recently uncovered an unexpected role for mRNA processing pathways in cellular adaptation to targeted therapy in melanoma cells. This is particularly intriguing given mRNA processing pathways are emerging as key determinants of gene expression programs activated in response to stress. Here, we investigated both transcriptional and post-transcriptional mechanisms underlying cellular adaptation to oncogenic BRAF inhibition by analyzing both mRNA abundance and mRNA bound to ribosomes, as a read out of mRNA translation. Consistent with previous studies, our analysis revealed a strong transcriptional component during the early response to BRAF inhibition, however notably, global analysis of the relationship between mRNA abundance and mRNA bound to ribosomes also indicated post-transcriptional modes of gene expression regulation during drug-induced adaptation. At a pathway level, our data provides evidence of an under-appreciated mode of gene expression regulation known as “translational buffering”, whereby discordance between mRNA abundance and levels of mRNA translation are observed. Intriguingly, this includes multiple metabolic pathways implicated in BRAF inhibitor response and resistance. As proof of concept, metabolomics analysis confirmed functional alterations in the melanoma metabolome consistent with post-transcriptional reprogramming of these pathways, supporting a key role for post-transcriptional mechanisms of gene regulation in the adaptive response to targeted therapy in melanoma cells. We propose that post-transcriptional mRNA processing pathways represent an attractive therapeutic target to improve efficacy of MAPK pathway inhibitors by targeting the process of adaptation itself, rather than the outcome, as a next generation combination therapy.