Evaluation, diagnosis, and treatment of children with Pervasive Developmental Disorder, Not Otherwise Specified (PDD NOS) is a daunting task. The core syndromic issues of problematic social relatedness and communication skills, variability of clinical course, multiple comorbidities, and lack of published treatment studies are just the beginning of the challenges faced by clinicians. This Clinical Case Conference presents an ecologically-based, comprehensive model of in-home treatment that shows promise of clinical effectiveness with this population. The presentation also emphasizes the importance of a collaborative, multi-domain, multi-systemic approach that is fully informed by the knowledge of the developmental psychopathology of PDD NOS.