The arteriolar myogenic response is crucial for the setting of vascular resistance and for providing a level of tone upon which vasodilators can act. Despite its physiological importance, questions remain regarding the underlying signaling mechanisms of the arteriolar myogenic response. Does an increase in pressure within an arteriole exert its effects via the extracellular matrix, an action on cell membranes and/or deformation of cytoskeletal structures? Recent advances in methodology, particularly involving sophisticated imaging approaches, are enabling the study of forces at single-cell and even subcellular levels. Atomic force microscopy (AFM) not only enables detection of cell morphology and stiffness but also allows discrete forces to be applied to single smooth muscle cells and subsequent responses to be observed. Importantly, the repertoire of approaches involving AFM can be expanded by using it in combination with other imaging approaches - including fluorescence imaging for cellular signals such as Ca(2+), and total internal reflectance fluorescence, fluorescence resonance energy transfer and confocal microscopy for probing cellular contact function. Combinations of these advanced imaging and nanomechanical approaches will be instructive to studies of intact vessels and the circulatory system in general.