Rab GTPases have been identified more than 20 years ago, and their central role as regulators of protein trafficking has attracted considerable attention to this protein family. Hundreds of Rabs have been described in the literature based on bioinformatics analysis, but only a small proportion has been experimentally characterized. Using the human Rab family as an example, we discuss here how our knowledge of the Rab universe is biased towards evolutionarily older, more highly and widely expressed proteins. Newly described Rab proteins have thus received little attention. We explore the types of functional and structural novelty that newly characterized Rabs are unveiling, and discuss the importance of these poorly characterized proteins by exploring their participation in human disease.