Anorexia nervosa (AN) is a severe psychiatric disorder without approved medication intervention. Every class of psychoactive medication has been tried to improve treatment outcome; however, randomized controlled trials have been ambiguous at best and across studies have not shown robust improvements in weight gain and recovery. Here we review the available literature on pharmacological interventions since AN came to greater public recognition in the 1960s, including a critical review of why those trials may not have been successful. We further provide a neurobiological background for the disorder and discuss how cognition, learning, and emotion-regulating circuits could become treatment targets in the future. Making every effort to develop effective pharmacological treatment options for AN is imperative as it continues to be a complex psychiatric disorder with high disease burden and mortality.