INTRODUCTION: Numerous therapeutics for neurological diseases have been developed, but many have failed in clinical trials in part due to limited brain bioavailability, mainly stemming from inefficient transport through the blood-brain barrier (BBB). One potential approach to noninvasive, BBB-targeted drug delivery to the brain is the use of engineered antibodies as delivery vehicles that can transport conjugated drug cargo across the BBB and into the brain via receptor-mediated transcytosis (RMT). Effective development of these RMT targeting systems includes novel target discovery, along with antibody engineering and subsequent validation. AREAS COVERED: This review focuses on both known and emerging RMT systems, targeting antibody properties in relation to BBB trafficking, and antibody validation strategies. EXPERT OPINION: Clinical development of known RMT targeting systems and identification of novel BBB RMT targets will be complementary strategies for overcoming the BBB in central nervous system (CNS) disease treatment. The search for new RMT targets with higher brain specificity and enriched expression in the brain has given rise to some new targets which may offer unique benefits. It is our opinion that the expansion of BBB RMT system identification, along with targeting molecule engineering and validation strategies, will substantially contribute to the treatment of a wide range of neurological diseases.