Epidemiological and clinical studies have uniformly reported an overrepresentation of females with very-late-onset schizophrenia-like psychotic disorder (VLOS), in stark contrast to the sex distribution of early-onset schizophrenia. Various explanatory models have been proposed to account for these sex differences, including (a) antidopaminergic effects of estrogen, (b) differential vulnerability to subtypes, (c) neurodegenerative differences between the sexes, and (d) and sex differences in age-related psychosocial and neurological risk factors; however, these models have not yet been critically evaluated for their validity. Keywords related to VLOS symptomatology, epidemiology, and sex/gender were entered into the PubMed, MEDLINE, and Google Scholar databases spanning all years. Through a narrative review of symptomatology and pathophysiology of VLOS, we examine the strengths and limitations of the proposed models. We present a comprehensive biopsychosocial perspective to integrate the above models with a focus on the role of neuroinflammation. There is significant room for further research into the mechanisms of VLOS that may help to explain the female preponderance; the effects of estrogen and menopause, neuroinflammation, and dopaminergic transmission; and their interaction with age-related and lifetime psychosocial stressors and underlying biological vulnerabilities.