Genetic factors play an important role in drug metabolism and drug response. In order to investigate genetic variables in lithium prophylaxis and lithium distribution across the erythrocyte in manic-depression, we have examined forty-two pairs of twins monozygotic (n = 25) and dizygotic (n = 17) with manic-depression. Concordant twins as a group show better lithium prophylaxis than do discordant twins. These results are consistent with previously published family studies of affective illness suggesting a positive relationship between genetic background and success of lithium prophylaxis. Lithium distribution across the red blood cell (RBC) was assessed by estimating lithium RBC/plasma ratios. The lithium ratio's intrapair differences in both groups of twins were minimal with a high heritability index suggesting that genetic factors play a role in lithium ion distribution. A high linear correlation was found between lithium ratio and plasma lithium and there was no difference in lithium ratios according to sex, affective state and response to lithium. The distribution of lithium ratios was homogenous in the lithium responders' population but this was not the case in the non-responders, suggesting biological heterogeneity of lithium distribution in lithium failures. The implications of these results are discussed as they relate to the genetic determinates of lithium prophylaxis in manic-depressive illness. These results indicate that lithium ratios are of limited value in lithium maintenance therapy. Our lithium kinetic data, however, are consistent with the concept of a lithium extrusion mechanism from red blood cells.