The α‐ and β‐myosin genes extend over 51 kb on chromosome 14 in human and 11 in mouse separated by about 4.5 kb of intergenic sequence. They are located in tandem in the order of their expression during development. Transcription of each gene is independently controlled but coordinately regulated. During each embryogenesis, the β‐MHC gene is expressed as part of the cardiac myogenic program under the control of NKX‐2.5, MEF‐2C, and GATA‐4/5/6. After birth, thyroid hormone induces expression of α‐MHC mRNA and inhibits expression of the β‐MHC gene. While a large number of physiological stimuli are capable of modifying this basic paradigm, thyroid hormone is required for expression of α‐MHC in ventricular muscle. The positive TRE for T₃‐stimulation of α‐MHC is an imperfect direct repeat located in the proximal promoter of the gene. The negative TRE for the β‐MHC gene is probably a binding half‐site that is located adjacent to the TATA box. Binding of TEF‐1 to a strong positive element in the proximal promoter is important in basal expression of β‐MHC gene and in the response to α₁‐adrenergic stimulation. The β‐MHC gene also is induced together with several other “fetal” genes during cardiac hypertrophy by a mechanism involving Ca²⁺‐mediated activation of calcineurin and NF‐AT3. Upon activation, NF‐AT3 translocates to the nucleus and interacts with GATA‐4 to stimulate β‐MHC expression. Changes in chromatin structure mediated by the association of histone acetylases and deacetylases with transcription factors are essential in regulating cell‐specific expression of MHC genes. Microsc. Res. Tech. 50:522–531, 2000. © 2000 Wiley‐Liss, Inc.