Schizophrenia (SCZ) and bipolar disorder (BD) share clinical characteristics and genetic risk. A useful insight into the pathophysiology of these disorders may derive from the study of intermediate phenotypes (IPs), biological traits that co-segregate with the disorders and are more prevalent in relatives of affected individuals compared to the general population. The goal of this chapter is to synthetize gray matter (GM) alterations in unaffected relatives of SCZ (SCZ-REL) and BD (BD-REL) to clarify the neural mechanisms underlying SCZ and BD, without the illness-related confounding factors. Current evidence shows that SCZ-REL are characterized by widespread GM alterations, mainly involving the frontal, parietal, and temporal lobes, thalamus, insula, and cerebellum, while BD-REL present GM abnormalities in the prefrontal, temporal, thalamic, limbic, and cerebellar areas. Similarly to SCZ and BD, SCZ-REL and BD-REL present a faster GM decline compared to healthy individuals. In conclusion, SCZ-REL and BD-REL present GM changes that lie between affected individuals and healthy subjects. Similar GM abnormalities in SCZ-REL and BD-REL may be the phenotypic expression of the shared genetic risk, while differences in GM alterations may be associated with disorder-specific features.