This chapter provides an overview of fundamental diagnostic and clinical considerations, discusses specific methodological issues relevant to panic treatment research, and reviews the current status of pharmacotherapy, psychotherapy, and combination treatment. The diagnosis of panic disorder (PD) can be made with or without agoraphobia, but whether agoraphobia occurs without antecedent PD is controversial. Clinical trial research in PD has typically emphasized reduction in frequency of attacks and percentage of patients panic-free as primary outcome measures. Imipramine and clomipramine have been the most extensively studied tricyclic antidepressants (TCAs) for PD. Relatively few studies have systematically evaluated exposure-based therapy alone for the treatment of PD. Most head-to-head comparisons of pharmacotherapy and cognitive-behavioral therapy (CBT) have shown either no differences or superiority of medication during acute treatment. Rigorous systematic studies are still needed in PD. Studying flawed existing trials can be enormously useful in improving the methodologies for future trials.