Although the cathecholamine systems have long been the focus of drug therapy in anxiety and depression, the development of novel drugs specifically aimed at new targets within these traditional neurotransmitter systems and at targets outside of these systems is now propelling the field of drug development in anxiety. A greater understanding of regional brain networks implicated in stress, anxiety, and anxious behaviors has provided localized targets for anxiolytics. Within the serotonin and norepinephrine systems, increased understanding of postsynaptic receptor regulation with chronic treatment and cross-system effects of drug therapy have been critical in furthering our understanding of effective pharmacological interventions. Receptors within the glutamate, gamma-aminobutyric acid, and neuropeptide systems provide a rich diversity of drug targets, both in localization and function. While acknowledging significant clinical and biological differences between the various anxiety disorders, an important aspect of modern neurobiological research is to look for similarities among these disorders, given that they are highly comorbid with each other and often respond to the same spectrum of treatments. Here we review current views on both traditional and new molecular targets in the treatment of anxiety, realizing that the ultimate challenge in effective anxiolytic drug development may be achieving specificity in brain regions important in generating and sustaining anxiety.