The review focuses on a widely-observed morphological phenomenon, a unique class of cytoplasmic vacuolation, found in cultured (mammalian) cells. This vacuolation is quite distinct from autophagosomal and heterophagosomal, i.e. excessive lysosomal vacuolation, and occurs in most cell types spontaneously or via a wide range of inductive stimuli. Apart from vacuolation arising artefactually (usually due to poor fixation), spontaneous vacuolation occurs in individual or small clusters of cultured cells without apparent change in their local environment, while neighbouring cells remain completely unaffected. Since spontaneous vacuolation is unpredictable, the process of vacuolation--or 'vacuolisation'--('Vacuolation' is the state of being with vacuoles; 'vacuolisation' therefore implies the process of becoming vacuolated. However, only the quicker term vacuolation will be used throughout this review to refer to the process of vacuole development.) induced experimentally, and hence relatively reproducibly by a range of substances and disturbances, offers an experimental approach which should give further insight into its physiology and pathophysiology. Unfortunately, our knowledge here remains woefully inadequate compared with the purely morphological aspects of the phenomenon. Vacuolation following disturbances could have an underlying common mechanism; however, a review of the literature suggests that this is not the case, and that it occurs via several different pathways, involving many different cell organelles and structures. All cells appear to retain the capacity to vacuolate for some physiological purpose, and it can be a permanent feature in many cell types, particularly 'lower' organisms and plants. Vacuolation in cells is generally seen as an adaptive physiological response, presumably for 'damage limitation', but very little is known about the intracellular homeostatic mechanisms which operate to restore the status quo. Where damage limitation fails, cells usually die quickly, but no clear evidence has been found that this is in any way 'programmed'. It is argued that the demise which occurs via the vacuolation route may, in fact, be a distinct form of cell death which is difficult to fit into the conventional lytic and apoptotic modes.