The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited and incurable neurodegenerative disorders primarily afflicting the pediatric population. Current treatment regimens offer only symptomatic relief and do not target the underlying cause of the disease. Although the underlying pathophysiology that drives disease progression is unknown, several small molecules have been identified with diverse mechanisms of action that provide promise for the treatment of this devastating disease. This review aims to summarize the current cellular and animal models available for the identification of potential therapeutics and presents the current state of knowledge on small molecule compounds that demonstrate in vitro and/or in vivo efficacy across the NCLs with an emphasis on targets of action.