Autistic Spectrum Disorders (ASDs) are a set of complex developmental disabilities defined by impairment in social interaction and communication, as well as by restricted interests or repetitive behaviors. Neuroimaging studies have substantially advanced our understanding of the neural mechanisms that underlie the core symptoms of ASDs. Nevertheless, a number of challenges still remain in the application of neuroimaging techniques to the study of ASDs. We review three major conceptual and methodological challenges that complicate the interpretation of findings from neuroimaging studies in ASDs, and that future imaging studies should address through improved designs. These include: (1) identification and implementation of tasks that more specifically target the neural processes of interest, while avoiding the confusion that the symptoms of ASD may impose on both the performance of the task and the detection of brain activations; (2) the inconsistency that disease heterogeneity in persons with ASD can generate on research findings, particularly heterogeneity of symptoms, symptom severity, differences in IQ, total brain volume, and psychiatric comorbidity; and (3) the problems with interpretation of findings from cross-sectional studies of persons with ASD across differing age groups. Failure to address these challenges will continue to hinder our ability to distinguish findings that outline the causes of ASDs from brain processes that represent downstream or compensatory responses to the presence of the disease. Here we propose strategies to address these issues: 1) the use of simple and elementary tasks, that are easier to understand for autistic subjects; 2) the scanning of a more homogenous group of persons with ASDs, preferably at younger age; 3) the performance of longitudinal studies, that may provide more straight forward and reliable results. We believe that this would allow for a better understanding of both the central pathogenic processes and the compensatory responses in the brain of persons suffering from ASDs.