This comprehensive literature review examines the evidence for and against an association between glucose or lipid dysregulation and second-generation (atypical) antipsychotics, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone, and aripiprazole. The review highlights that substantial evidence from various human populations indicates that increased adiposity is associated with adverse physiological effects, including decreased insulin sensitivity and changes in glucose and lipid levels. Weight gain liability varies significantly among the different antipsychotic agents, with clozapine and olanzapine showing the highest risk of clinically significant weight gain, while ziprasidone and aripiprazole have the lowest risk. Published studies, including uncontrolled observations, retrospective database analyses, and controlled experimental studies, suggest that different second-generation antipsychotics have varying effects on glucose and lipid metabolism. Clozapine and olanzapine are associated with an increased risk of diabetes mellitus and dyslipidaemia, while risperidone and quetiapine show limited or no increased risk. The absence of data from large retrospective database analyses for zotepine and amisulpride makes it difficult to draw conclusions. Ziprasidone and aripiprazole do not show evidence of increased risk for diabetes, dyslipidaemia, or other adverse effects on glucose or lipid metabolism. The differing weight gain liabilities of atypical antipsychotics contribute to the varying relative risks of insulin resistance, dyslipidaemia, and hyperglycaemia. However, case reports suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes during treatment. Limited controlled studies support the hypothesis that clozapine and olanzapine may have a direct effect on glucose regulation independent of adiposity. The review addresses several key questions regarding the risk of diabetes and dyslipidaemia associated with second-generation antipsychotics, including whether these risks differ between agents and if they are related to body weight or adiposity. The findings are relevant to primary and secondary prevention efforts aimed at reducing the prevalence of type 2 diabetes mellitus and cardiovascular disease in populations treated with these medications.This comprehensive literature review examines the evidence for and against an association between glucose or lipid dysregulation and second-generation (atypical) antipsychotics, specifically clozapine, olanzapine, risperidone, quetiapine, zotepine, amisulpride, ziprasidone, and aripiprazole. The review highlights that substantial evidence from various human populations indicates that increased adiposity is associated with adverse physiological effects, including decreased insulin sensitivity and changes in glucose and lipid levels. Weight gain liability varies significantly among the different antipsychotic agents, with clozapine and olanzapine showing the highest risk of clinically significant weight gain, while ziprasidone and aripiprazole have the lowest risk. Published studies, including uncontrolled observations, retrospective database analyses, and controlled experimental studies, suggest that different second-generation antipsychotics have varying effects on glucose and lipid metabolism. Clozapine and olanzapine are associated with an increased risk of diabetes mellitus and dyslipidaemia, while risperidone and quetiapine show limited or no increased risk. The absence of data from large retrospective database analyses for zotepine and amisulpride makes it difficult to draw conclusions. Ziprasidone and aripiprazole do not show evidence of increased risk for diabetes, dyslipidaemia, or other adverse effects on glucose or lipid metabolism. The differing weight gain liabilities of atypical antipsychotics contribute to the varying relative risks of insulin resistance, dyslipidaemia, and hyperglycaemia. However, case reports suggest that substantial weight gain or obesity may not be a factor in up to one-quarter of cases of new-onset diabetes during treatment. Limited controlled studies support the hypothesis that clozapine and olanzapine may have a direct effect on glucose regulation independent of adiposity. The review addresses several key questions regarding the risk of diabetes and dyslipidaemia associated with second-generation antipsychotics, including whether these risks differ between agents and if they are related to body weight or adiposity. The findings are relevant to primary and secondary prevention efforts aimed at reducing the prevalence of type 2 diabetes mellitus and cardiovascular disease in populations treated with these medications.