Muscle wasting in patients with sepsis, severe injury, and cancer is associated with increased transcription of several genes regulating different proteolytic pathways. The involvement of gene activation in muscle wasting suggests that transcription factors and nuclear cofactors play important roles in the regulation of muscle mass. Among transcription factors, NF-κB, C/EBPβ, and FOXO transcription factors are activated in atrophying muscle and stimulate the transcription of genes in the ubiquitin-proteasome proteolytic pathway, as well as genes regulating authophagy/lysosomal proteolysis. Changes in the expression and activity of several nuclear cofactors, including the histone acetyltransferase p300, histone deacetylases (HDACs), such as HDAC3, HDAC6, and SIRT1, as well as the nuclear cofactors PGC-1α and β, contribute to loss of muscle mass in various catabolic conditions. The activity of transcription factors and nuclear cofactors involved in the regulation of muscle mass is influenced not only by their abundance, but also by posttranslational modifications as well, including ubiquitination, phosphorylation, and acetylation. Transcription factors and nuclear cofactors involved in muscle wasting interact with each other at multiple levels, supporting the concept that the molecular regulation of muscle mass in various catabolic conditions is complex. An increased understanding of molecules that modulate gene transcription in catabolic muscle may make it possible to develop treatments targeting transcription factors and nuclear cofactors in the prevention and treatment of muscle wasting.