Structural designability is the number of ways it is possible to encode for structure. A protein’s designability has been equated with the size of sequence space encoding for the protein’s structure, a measure that reflects the structure’s robustness to mutation. Current evidence suggests that designability is fundamental to our understanding of the evolvability and distribution of structures in nature and is a significant factor associated with human disease. Here, we describe definitions and principles underlying the concept of designability and discuss its relation to disease.