The mechanism by which cells sense stresses and transmit them throughout the cytoplasm and the cytoskeleton (CSK) and by which these mechanical signals are converted into biochemical signaling responses is not clear. Specifically, there is little direct experimental evidence on how intracellular CSK structural elements in living cells deform and transmit stresses in response to external mechanical forces. Existing theories have invoked various biophysical and biochemical mechanisms to explain how cells spread, deform, divide, move, and change shape in response to mechanical inputs, but rigorous tests in cells are lacking. The lack of data and understanding is preventing the identification of mechanisms and sites of mechano-regulation in cells. Here, we introduce and describe three unique and easy methods for biologists to determine mechanical properties and signaling events in cells.