Diagnosis and treatment of the PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) variant of Gilles de la Tourette syndrome (GTS) and childhood-onset obsessive-compulsive disorder (OCD) are still controversial issues. Most cross-sectional studies confirm a significant association between GTS and the development of an immune response against group A beta-hemolytic streptococcus (GABHS). Moreover, longitudinal retrospective studies suggest that a recent exposure to GABHS might be a risk factor for the onset of tics and obsessive-compulsive symptoms. However, further evidence from longitudinal prospective research is needed to verify whether a temporal association between GABHS infections and symptom exacerbations is a useful and reliable criterion for the diagnosis of PANDAS. In addition, preliminary results suggest that the PANDAS spectrum might be enlarged to include attention deficit/hyperactivity disorder. Although a number of immunological biomarkers have been proposed as markers of the PANDAS variant, at present, none of these has been conclusively proved useful to diagnose and monitor disease course in children with a suspicion of PANDAS. Finally, despite their empirical use in community settings, we still lack conclusive, evidence-based data regarding the usefulness of antibiotic and immunomodulatory treatments in children with PANDAS. Given the relevance of this topic for general pediatric health, additional research efforts to solve all the pending issues and the hottest points of debate are warranted.