Copyright © 2014 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Purpose of review Recent studies clearly demonstrate that copy number variations (CNVs) are widespread in our genome and play an important role in human genetic variation, accounting for both human population diversity and human genetic disease. This review will discuss the most current knowledge regarding our understanding of the biology of CNVs in relation to human genetic disease. Recent findings CNVs associated with human genetic disease can be either recurrent, with a common size and breakpoint clustering, or nonrecurrent, with different sizes and variable breakpoints. Two types of recurrent CNVs have been distinguished, including the syndromic forms in which the phenotypic features are relatively consistent, and those in which the same recurrent CNV can be associated with a diverse set of diagnoses. Recently, the 'Two-hit model' was used to explain the phenotypic variability associated with the latter group of recurrent CNVs. Nonrecurrent CNVs, on the contrary, occur at a relatively lower frequency at the individual locus level but collectively they are as common as recurrent CNVs. Finally, the study of CNV burden in different diseases demonstrated a clear trend of an increasing CNV burden in diseases with more severe phenotypes. Summary In spite of the advances in the study of the CNV landscape associated with human genetic disease, there still remain many unexplored questions especially regarding the role of CNVs in the pathogenesis of complex human genetic diseases.