Liquid biopsies have revolutionized the field of oncology and are especially appealing as they provide a minimally invasive method of obtaining tumor information. This enables serial sampling of tumor information, allowing real-time molecular profiling. Liquid biopsy companion diagnostic tests have been approved by the U.S. Food and Drug Administration (FDA) for several adult cancers, with applications that include directing targeted therapies. In pediatric cancers, there has been a lag in liquid biopsy clinical applications, with most studies being performed retrospectively and not yet making a widespread impact on patient care. However, studies demonstrate that this technology has substantial potential in redefining and, in some cancers, introducing personalized medicine approaches to pediatric clinical oncology. This chapter will discuss the rise of two promising liquid biopsies, aqueous humor and blood, for the most common pediatric ocular cancer, retinoblastoma.