Extraocular muscle exhibits higher-velocity and lower-tension contractions than other vertebrate striated muscles. These distinctive physiological properties are associated with the expression of a novel extraocular myosin heavy chain (MYH). Encoded by the MYH13 gene, the extraocular myosin heavy chain is a member of the fast/developmental MYH gene cluster on human chromosome 17 and the syntenic MYH cluster on mouse chromosome 11. Comparison of cDNA sequences reveals that MYH13 also encodes the atypical MYH identified in laryngeal muscles, which have similar fast contractile properties. Comparing the MYH13 sequence with the other members of the fast/developmental cluster, the slow/cardiac MYH genes and two orphan skeletal MYH genes in the human genome provides insights into the origins of specialization in striated muscle myosins. Specifically, these studies indicate (i) that the extraocular myosin is not derived from the adult fast skeletal muscle myosins, but was the first member of the fast/developmental MYH gene cluster to diverge and specialize, (ii) that the motor and rod domains of the MYH13 have evolved under different selective pressures and (iii) that the MYH13 gene has been largely insulated from genomic events that have shaped other members of the fast/developmental cluster. In addition, phylogenetic footprinting suggests that regulation of the extraocular MYH gene is not governed primarily by myogenic factors, but by a hierarchical network of regulatory factors that relate its expression to the development of extraocular muscles.