Delusional beliefs are seen in association with a number of neuropathological conditions, including schizophrenia, dementia, and traumatic brain injury. A key distinction exists between polythematic delusion (here the patient exhibits delusional beliefs about a variety of topics that are unrelated to each other) and monothematic delusion (here the patient exhibits just a single delusional belief or else a small set of delusional beliefs that are all related to a single theme). A great deal of recent research has focused on identifying and investigating various different forms of monothematic delusion. We discuss a general theoretical approach to the understanding of monothematic delusions—a two-factor approach according to which understanding the nature and genesis of any kind of monothematic delusion involves seeking answers to two questions. The first question is, what brought the delusional idea to mind in the first place? The second question is, why is this idea accepted as true and adopted as a belief when the belief is typically bizarre and when so much evidence against its truth is available to the patient? We discuss in detail six different kinds of monothematic delusion, showing for each how neuropsychological considerations allow a first factor (responsible for the content of the belief) and a second factor (responsible for the failure to reject the belief) to be plausibly identified. Five difficulties confronting this two-factor account of monothematic delusion are then identified, and attempts are made to address each one.