The mechanotransduction mechanisms play an important role in regulation of specific cellular response or maintenance of cellular homeostasis in a wide variety of cell types. Increase in intracellular free Ca(2+) concentration ([Ca(2+)](i)) is an important signal in the first step of mechanotransduction. Mechanosensitive (MS) cation channels are thought to be a putative pathway of Ca(2+) entry; however, the molecular mechanisms remain unclear. We have previously demonstrated that lysophosphatidic acid (LPA), a bioactive phospholipid present in human plasma, sensitizes the response of [Ca(2+)](i) to mechanical stress in cultured smooth muscle cells, cultured lung epithelial cells, and cultured lens epithelial cells. Using real-time confocal microscopy, local increases in [Ca(2+)](i) in several regions within the cell subjected to mechanical stress were clearly visualized in cultured bovine lens epithelial cells and cultured vascular endothelial cells in the presence of LPA. We called the phenomenon "Ca(2+) spots". Pharmacological studies revealed that the Ca(2+) spot is an elementary Ca(2+)-influx event through MS channels. In this review, possible physiological and pathophysiological roles of LPA as a mechanosensitizer are discussed.