Signal transducers and activators of transcription (STATs) are latent cytoplasmic transcription factors that mediate various biological responses, including cell proliferation, survival, apoptosis, and differentiation. Among the members of the STAT family, accumulating evidence now indicates an important role for STAT1 in various forms of cell death. Depending upon stimuli or cell types, STAT1 can modulate a broad spectrum of cell death, comprising both apoptotic and non-apoptotic pathways. STAT1-dependent regulation of cell death is largely dependent on a transcriptional mechanism such as the activation of death-promoting genes. However, non-transcriptional mechanisms such as STAT1 interaction with TRADD, p53, or HDAC have been implicated in the regulation of cell death by STAT1. Furthermore, STAT1 itself is also subject to complex forms of regulation such as post-translational protein modification, which can critically affect STAT1 signaling and STAT1-dependent cell death. Given the reports showing that dysregulation of STAT1 signaling is associated with various pathological conditions, including the development of cancer, a better understanding of the mechanism underlying STAT1 regulation of cell death may lead to successful strategies for targeting STAT1 in such pathological settings.