’Divide and conquer’ has been the guiding strategy for the study of protein structure and function.Proteins are divided into domains with each domain having a canonical structural definition depending on its type.In this review,we push forward with the interesting observation that many domains have regions outside of their canonical definition that affect their structure and function;we call these regions ’extensions’.We focus on the highly abundant PDZ(PSD-95,DLG1 and ZO-1)domain.Using bioinformatics,we find that many PDZ domains have potential extensions and we developed an openly-accessible website to display our results(http://bcz102.ust.hk/pdzex/).We propose,using well-studied PDZ domains as illustrative examples,that the roles of PDZ extensions can be classified into at least four categories:1)protein dynamics-based modulation of target binding affinity,2)provision of binding sites for macro-molecular assembly,3)structural integration of multi-domain modules,and 4)expansion of the target ligand-binding pocket.Our review highlights the potential structural and functional importance of domain extensions,highlighting the significance of looking beyond the canonical boundaries of protein domains in general.