Both the hexosamine biosynthetic pathway (HBP) and the endoplasmic reticulum (ER) are considered sensors for the nutritional state of the cell. The former is a branch of the glucose metabolic pathway that provides donor molecules for glycosylation processes, whereas the second requires co-translational N-glycosylation to ensure proper protein folding. It has become clear that the microenvironment of solid tumours, characterised by poor oxygen and nutrient supply, challenges optimal functions of the ER and the HBP. Here, we review recent advances demonstrating that the ER stress (ERS) response and HBP pathways are interconnected to promote cell viability. We then develop the idea that communication between ER and HBP is a survival feature of neoplastic cells that plays a prominent role during tumourigenesis.