Bipolar disorder (BD) is worldwide a prevalent mental illness and a leading risk factor for suicide. Over the past three decades, it has been discovered that sex differences exist throughout the entire panorama of BD, but the etiologic regions and mechanisms that generate such differences remain poorly characterized. Available evidence indicates that the dorsolateral prefrontal cortex (DLPFC), a critical region that controls higher-order cognitive processing and mood, exhibits biological disparities between male and female patients with psychiatric disorders, which are highly correlated with the co-occurrence of psychotic symptoms. This review addresses the sex differences in BD concerning epidemiology, cognitive impairments, clinical manifestations, neuroimaging, and laboratory abnormalities. It also provides strong evidence linking DLPFC to the etiopathogenesis of these sex differences. We emphasize the importance of identifying gene signatures using human brain transcriptomics, which can depict sexually different variations, explain sex-biased symptomatic features, and provide novel targets for sex-specific therapeutics.