The electrophysiological properties of peripheral neurons activated by noxious stimuli, the primary afferent nociceptors, have been investigated intensively, and our knowledge about the molecular basis of transducers for noxious stimuli has increased greatly. In contrast, understanding of the intracellular signaling mechanisms regulating nociceptor sensitization downstream of ligand binding to the receptors is still at a relatively nascent stage. After outlining the initiated signaling cascades, we discuss the emerging plasticity within these cascades and the importance of subcellular compartmentalization. In addition, the recently realized importance of functional interactions with the extracellular matrix, cytoskeleton, intracellular organelles such as mitochondria, and sex hormones will be introduced. This burgeoning literature establishes new cellular features crucial for the function of nociceptive neurons and argues that additional focus should be placed on understanding the complex integration of cellular events that make up the "cell biology of pain."