Recent advances in technology for detecting copy number changes have enabled genome-wide detection of submicroscopic deletions and duplications. As these technologies are applied to large cohorts of patients with diverse phenotypes, novel genomic disorders are defined by a common genotype (deletion or duplication) rather than a common phenotype. The discovery of new genomic disorders using this "genotype-first" approach has increased dramatically, and several recently described recurrent rearrangements are associated with a surprisingly wide range of phenotypes. This review will discuss the importance of genomic architecture for generating recurrent rearrangements, implications of the genotype-first approach for medical genetics, and features of several new genomic disorders with highly variable phenotypes.