Psoriasis is a complex, immune-mediated inflammatory disease that occurs in genetically susceptible individuals and affects approximately 2.2% of the world's population. It typically manifests on the skin and joints but is also associated with a number of comorbid diseases leaving negative consequences on the quality of life of patients, especially those with moderate to severe form. Given the presence of comorbidities, treatment side effects, different patient preferences and frequent noncompliance, treating psoriasis remains a major challenge. In most cases, treatment involves the use of topical agents, phototherapy and conventional systemic medications but advances in understanding the pathophysiology of psoriasis have led to the development of new highly effective targeted treatments. Biologics and small synthetic molecules have revolutionized the treatment of psoriasis thanks to their excellent efficacy, favorable safety profile and improved patient adherence. Although they do not show the effectiveness of biologics, small molecules have certain advantages such as oral and topical administration, lower risk of severe side effects and more favorable price. Biologics and small molecules approved for the treatment of plaque psoriasis include: TNF-α antagonists, IL-17 inhibitors, IL-12 and IL-23 inhibitors, IL-23 inhibitors, PDE-4 inhibitor (apremilast) and fumaric acid ester (dimethyl fumarate). Numerous other biologics and small molecules currently under development show promising efficacy and the potential to become safer alternatives to currently available therapies.