Introduction: Panic disorder (PD) is a common disabling anxiety disorder associated with relevant social costs. Effective anti-panic medications exist but have several drawbacks. From a clinical perspective, there is still a strong unmet need for more effective, faster acting and more tolerable therapeutic treatments. Areas covered: The authors review the available results on novel mechanism-based anti-panic drugs that are under investigation in animal studies up to Phase II studies. The preclinical studies investigated include: the modulators of the glutamate/orexin/cannabinoid systems, corticotrophin-releasing factor 1 (CRF1)/arginine vasopressine V1B/angiotensin II receptor antagonists and neuropeptide S. The Phase I/II studies investigated include: the modulators of the glutamate system, isoxazoline derivative, translocator protein (18 kDa) ligands and CRF1/neurokinin receptor antagonists. Expert opinion: There has been little progress in recent times. However, glutamate- and orexin-related molecular targets may represent very promising opportunities for treating panic attacks. Very preliminary findings suggest that the antagonists of CRF1 and A-II receptors may have anti-panic properties. However, new medications for PD are far from being implemented in clinical use. The reasons are multiple, including: the heterogeneity of the disorder, the translational validity of animal models and the insufficient use of biomarkers in preclinical/clinical studies. Nevertheless, biomarker-based strategies, pharmacogenomics, ‘personalized psychiatry’ and the NIH’s Research Domain Criteria approach could help to remove those obstacles limiting drug development.