The transcription factors nuclear factor-κB (NF-κB) and activating protein-1 (AP-1) are critical regulators of stress responses, immunity, inflammation and cancer. A large variety of cellular stimuli utilize these signaling pathways through a common upstream kinase transforming growth factor-β-activated kinase 1 (TAK1). TAK1 was originally identified as a mitogen-activated kinase kinase kinase (MAP3K) activated by transforming growth factor-β (TGF-β); however, it has been characterized as a key regulator in inflammatory and immune signaling pathways. In addition, microbial proteins and components of host cell signaling scramble for the TAK1 complex in innate immunity. This review highlights the recent advances in the activation mechanisms and physiological functions of TAK1. Research targeting TAK1 raises the potential for new therapeutic options for inflammatory disorders, including cancer.