The UPR (unfolded protein response) has been identified as a key factor in the progression and metastasis of cancers, notably melanoma. Several mediators of the UPR are upregulated in cancers, e.g., high levels of GRP78 (glucose-regulator protein 78 kDa) correlate with progression and poor outcome in melanoma patients, indicating that the UPR promotes tumourigenesis and metastasis. AMPylation of GRP78, the covalent addition of adenosine monophosphate (AMP), has recently been identified and may modulate the UPR cascade. Utilising immunoaffinity and mass spectrometry we have identified differential AMPylation of several key UPR proteins in response to increased UPR in human melanoma cell lines Mel-RM and SK-Mel-28. The complete role of the UPR has yet to be defined. Understanding how the UPR allows for adaption to stress and thereby assists in cancer progression is important in defining an archetype of melanoma pathology. In addition, targeting AMPylation of key UPR proteins could prove an effective treatment against melanoma.