This chapter emphasizes the importance of adequate care of pharmacological evidence on treating panic disorder. It focuses on the optimal first-line pharmacotherapy of panic disorder. The chapter discusses the optimal duration of maintenance therapy, and describes the optimal approach to pharmacotherapy in the treatment-refractory patient. It reviews the antidepressants and benzodiazepines with regard to efficacy in acute and long-term treatment, the side-effects and risks involved, drop-out rates, onset of action and efficacy in comorbid conditions. Given the comparable efficacy of the pharmacological classes described in acute phase treatment and the efficacy in long-term treatment, other considerations determine which agent should be considered the first-line pharmacotherapy of panic disorder. The first-line pharmacotherapy for panic disorder has been selective serotonin reuptake inhibitor (SSRIs) for some time, and there is now sufficient evidence to indicate that the SNRI venlafaxine should also be considered as a first-line agent.