Integration of the cell signaling circuitry determines the ultimate response of a cell to extracellular stimuli. The transcription factor nuclear factor-kappa B (NF-kappaB) and mitogen-activated protein kinase JNK1 are major players in the cell signaling circuitry, regulating numerous cellular events and being implicated in the process of many human diseases and certain types of cancer. The interplay between NF-kappaB and JNK1 provides a paradigm that shows how the crosstalk between different signaling pathways decides the function of the cell signaling circuitry. Understanding the wiring of the cell signaling circuitry may hold the key for cell signaling-based therapy of human diseases.