Over two thousand proteins are found in the mitochondrial compartment but the mitochondrial genome codes for only 13 proteins. The majority of mitochondrial proteins are products of nuclear genes and are synthesized in the cytosol, then translocated into the mitochondria. Most of the subunits of the five respiratory chain complexes in the inner mitochondrial membrane, which generate a proton gradient across the membrane and produce ATP, are encoded by nuclear genes. Therefore, it is quite clear that import of nuclear-encoded proteins into the mitochondria is essential for mitochondrial function. Nuclear to mitochondrial communication is well studied. However, there is another arm to this communication, mitochondria to nucleus retrograde signaling. This plays an important role in the maintenance of cellular homeostasis, and is less well studied. Several transcription factors, including Sp1, SIRT3 and GSP2, are activated by altered mitochondrial function. These activated transcription factors then translocate to the nucleus. Based on the mitochondrially generated molecular signal, nuclear genes are targeted, which alters transcription of nuclear genes that code for mitochondrial proteins. This review article will mainly focus on this interactive and bi-directional communication between mitochondria and nucleus, and how this communication plays a significant role in muscle cell biology.