Tubular mechanical stretch is the key primary insult in obstructive nephropathy. This review addresses how the renal tubular epithelium senses and responds to mechanical stretch. Using data from renal and nonrenal systems, we describe how sensing of stretch initially occurs via the activation of ion channels and subsequent increases in intracellular calcium levels. Calcium influxes activate a number of adaptive and proinjury responses. Key among these are 1) the activation of Rho, consequent cytoskeletal rearrangements, and downstream increases in focal adhesion assembly; and 2) phospholipase activation and resultant mitogen-activated protein kinase activation. These early signaling events culminate in adaptive cellular coupling to the extracellular matrix, a process termed the cell strengthening response. Direct links can be made between increased expression of genes involved in the development of obstructive nephropathy and initial sensing of mechanical stretch. The review illustrates the repercussions of mechanical stretch as a renal stress stimulus, specific to ureteric obstruction, and provides an insight into how tubular responses to mechanical stretch are ultimately implicated in the development of obstructive nephropathy.