GCN2 activation and EIF2A phosphorylation have far-reaching consequences for cellular physiology in response to a number of stresses. The current understanding of GCN2 function and regulation largely stems from studies on starvation responses in budding yeast. The GCN2 pathway is emerging as an attractive target for therapy in diseases such as cancer and possibly Alzheimer’s disease. Understanding more about its functions and its involvement in the regulation of selective translation could reveal its full potential for clinical applications.