The roles of nuclear factor of activated T cells (NFAT) transcription factors have been extensively studied in the immune system. However, ubiquitous expression of NFAT isoforms in mammalian tissues has recently been observed, and a role for these transcription factors in human cancer is emerging. Various NFAT isoforms are functional in tumour cells and multiple compartments in the tumour microenvironment, including fibroblasts, endothelial cells and infiltrating immune cells. How do NFAT isoforms regulate the complex interplay between these compartments during carcinoma progression? The answers lie with the multiple functions attributed to NFATs, including cell growth, survival, invasion and angiogenesis. In addition to elucidating the complex role of NFATs in cancer, we face the challenge of targeting this pathway therapeutically.