Apoptosis is a physiological form of death in which cells turn-on an intrinsic genetic program that eventually leads to their destruction in a highly regulated manner. This process renders elimination of "unwanted cells" in the body, and accounts for cellular turnover and homeostasis of tissues in multicellular organisms. Consequently, an imbalance in the apoptotic rate in a particular tissue can lead to profound effects in the whole organism. Exposure of cells to apoptotic stimuli induces a rapid loss of cell volume (apoptotic volume decrease) that plays a pivotal role in the decision of a cell to undergo apoptosis. Interestingly, the apoptotic volume decrease is driven by changes in ionic fluxes across the plasma membrane that promote a decrease in the intracellular ions that ultimately also leads to a reduction in intracellular ionic strength. Despite an intensive research effort however, the cellular and molecular mechanisms that trigger changes in cell volume during apoptosis remain poorly understood. Nevertheless, this apoptotic volume decrease has been shown to be a necessary component of the apoptotic cascade and an important point of modulation for the entire cell death process. In this review, we will focus on the importance of the apoptotic volume decrease in the context of signaling and modulation of programmed cell death.