Since Kanner's original description of autism, it has become evident that the range and form of manifestations are much more extensive and complex than first thought. Autism is the prime example of what is now often referred to as the autism spectrum disorders. Causation is complex and varied and many important questions about the causes and manifestations remain puzzling and unanswered. Explanations for some of the key questions will potentially lead to significant new insights and advances.

• Why do some people with autism spectrum disorder have learning disability or language impairments, but others do not? 
• Why do some children with autism spectrum disorders show a regression in development in the early years?
• Why do about 25-30% of children with autism spectrum disorders develop epilepsy?
• Why do some genetic conditions (e.g. tuberous sclerosis, fragile X, abnormalities of chromosome 15) and developmental brain disorders and epilepsy syndromes (e.g. infantile spasms) commonly give rise to autism spectrum disorders while others do not (e.g. Down syndrome, cerebral palsy)?
• Why do only subsets of individuals with specific genetic conditions, brain disorders or epilepsy syndromes (e.g. tuberous sclerosis) develop autism spectrum disorders?
• What are the environmental / non genetic causes of autism?
• What was it about the extreme deprivation experienced by the Romanian orphans that led to the development of quasi- autistic symptomatology?
• Why do children with autism have an unusual pattern of brain development with an excessive spurt in brain growth in the early years?
• Are autism and the variants of autism best considered to represent a distinct syndrome that is due to a specific set of causes or does autism and autistic symptomatology represent an extreme variation of normality (just as obesity can be considered an extreme variant of normal weight or hypertension an extreme variation in normal blood pressure)?
• Why do so many more males than females develop autism spectrum disorders?
• Why are individuals with autism spectrum disorders prone to attention deficit hyperactivity disorder (ADHD), motor tics, Tourette's syndrome, obsessive-compulsive disorders and mood disturbances?
• For people with autism spectrum disorder, what issues emerge in middle and later life?

These represent a selection of the most enigmatic aspects of autism and related disorders, but there are many other unanswered questions. Clearly, answers to these and other questions will only come from the dedicated effort of an interdisciplinary group of basic and clinical scientists working closely together with clinical colleagues.