In this review, we discuss the involvement of ubiquitination in the regulation of the epidermal growth factor (EGF)-mediated extracellular signal-regulated kinase (ERK) signalling pathway via the EGF receptor (EGFR), and highlight the interplay between ubiquitination and phosphorylation in this system, which beyond its many physiological functions is also a major player in human cancer. The gene discussed is MAPK1; the disease is cancer.