Nuclear factor κB (NF-κB) is a well-known pro-inflammatory transcription factor that regulates the expression of the tissue’s immune-active components, which include cytokines, chemokines and adhesion molecules. In addition, the versatile nuclear factor of activated T-cells (NFAT) family of transcription factors plays a crucial role in the development and function of the immune system, integrating calcium signaling with other signaling pathways. NF-κB and NFAT share many structural and functional characteristics and likely regulate gene expression through shared enhancer elements. This review describes recent research data that has led to new insights into the involvement of NFκB- and NFAT-mediated pathways in the different idiopathic inflammatory myopathies. The general activation of NF-κB p65 in blood vessel endothelium, seems to flag down inflammatory cells that subsequently accumulate mostly at perimysial sites in dermatomyositis. The joint activation of p65 and NFAT5 in myofibers specifically at perifascicular areas reflects the characteristic tissue damage pattern observed in that particular subgroup of patients. In immune cells actively invading nonnecrotic muscle fibers in polymyositis and sporadic inclusion body myositis on the other hand, p65 activation is an important aspect of their cytotoxic and chemoattactant properties. In addition, both transcription factor families are generally upregulated in regenerating muscle fibers as components of the differentiation process. It can be concluded that the two transcription factor families function in close relationship with each other, representing two-edged swords for muscle disease: on the one hand promoting cell growth and regeneration, while on the other hand actively participating in inflammatory cell damage. In this respect, cytokines function as important go-betweens at the crossroads of the pathways. Beyond NF-κB and NFAT, many fascinating winding roads relevant to inflammatory myopathy disease management still lie ready for the exploring.