Skeletal ligaments are well characterized as mechanical stabilizers of diarthrodial joints. New evidence now suggests that the normal regulation of ligament and joint function may occur through a neural and microvascular “axis,” where the physiology of normal ligaments is influenced by heterogeneous cellular, neural, and microvasculature elements. Within ligament tissue, complex networks of cellular processes linked by gap junctions allow the direct cell-to-cell transfer of signaling molecules, whereas sensory innervation and neurovascular reflexes contribute to motor control and affect ligament mechanical properties. The application of new imaging technologies may assist in determining the functional implications of an integrated neural and microvascular axis. Aging and gender related differences in ligament function are also discussed.