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Successful treatment of individuals with autism spectrum disorders (ASD) is entirely contingent on an accurate diagnosis. Although many resources exist to help the clinician with differential diagnosis of children, particularly in early childhood, the resources available for evaluating adolescents and adults is far less prevalent. Clinicians often rely on multiple forms of data from numerous sources to make accurate diagnoses, which for adults is a complex process. Lack of availability of instruments that have been normed with individuals with ASD creates limitations for the clinician. In addition, gathering background information from adolescents and adults on the spectrum can be challenging for a number of reasons, including poor self-reporting and poor memory for events from parents or caregivers. To further complicate the matter, comorbid conditions become more and more common as the individual with ASD goes through adolescence and adulthood. This article aims to identify the challenges related to the evaluation of adolescents and adults with ASD, noting particular attention to the differential diagnosis of common comorbid conditions. Recommendations for how to conduct a thorough psychological evaluation with an adolescent or adult with an ASD are made.