Regulation of protein synthesis makes a major contribution to post-transcriptional control, and during disease or following cell stress, reprogramming of the translatome is essential to orchestrate the appropriate cellular response [1]. Protein synthesis is a three-stage process of initiation (where eukaryotic initiation factors (eIFs) bind to the RNA and recruit the ribosome), elongation (when tRNA-dependent and eEF1A-dependent codon decoding, and eEF2-dependent ribosome translocation occurs to produce the polypeptide chain) and termination (where upon reaching a stop codon, the polypeptide chain is released from the ribosome) [2]. Both initiation and elongation phases are highly regulated by changes in the phosphorylation status of eIFs or eEFs, and these processes combine to determine the overall rate of translation [2,3]. Initiation is for the most part controlled by changes in the phosphorylation status of 4EBPs and eIF2a. 4EBPs are regulated by mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that is inhibited in response to cellular stress such as DNA damage, low energy levels and hypoxia [4]. Upon mTOR inhibition 4EBPs are dephosphorylated and sequester the cap-binding protein eIF4E, reducing protein synthesis rates [5]. However, following stimulation with growth factors and amino acids, upstream signalling pathways including PI3K/AKT and MAPK, activate mTOR to enhance phosphorylation of 4EBPs and the release of eIF4E, stimulating protein synthesis. EIF2 is required for the formation of ternary complex (TC) with GTP and tRNAimet, which is necessary to recruit the initiator methionine to the start codon. When phosphorylated on the alpha subunit, eIF2 binds to its GEF eIF2B, inhibiting its activity and reducing the amount of TC available. There are four mammalian kinases that control the phosphorylation of eIF2: PERK, PRK, GCN2 and HRI [6,7]. Each kinase is activated by specific stress stimuli, however many stresses activate more than one kinase. For example, both hyperosmotic stress and double-stranded RNA, activate PKR [8,9]. Elongation is controlled by regulating tRNA levels, in addition to the phosphorylation of eEF2 by eEF2K, which prevents ribosome translocation along the mRNA [3]. Interestingly, eEF2K is activated by Ca2+/CaM and signalling downstream of AMPK, whereas it is inactivated by signalling through mTORC1 [10], enabling mTOR to regulate both initiation and elongation. Many of the environmental stresses that modify the canonical protein synthesis machinery in response to external stress are also important for survival of a tumour cell. Two major stress response pathways that are modulated in tumours are the unfolded protein response (UPR) and the DNA damage response (DDR) (summarised in Figure 1). Here, we will discuss the recent findings identifying how post-transcriptional control pathways downstream of the UPR/DDR are modulated in cancer, and discuss translational reprogramming within tumours and its implication for future therapy.