Although one can delineate some trends in current thinking, we should reflect on the ability of working scientists to predict the future. It is poor.* Therefore, though trends now seem to be identifiable with relative clarity, we recognize that fields change rapidly, and we acknowledge that the topic discussed here represents a certain level of hubris. Nevertheless, the last 10 years have seen some remarkable changes. From an original description of apoptosis as inherently a phenomenon of morphology, we have moved to a much more comprehensive understanding of the molecular origins of that morphology, including at least partial understanding of the roles of proteases and nucleases in creating the hallmarks of apoptosis. Many of these advances derive from the cloning and identification of Caenorhabditis genes, which opened the entire horizon of proteases, and led directly to identification of the role of mitochondria in apoptosis. 1±10 Similarly, identification of pro-and anti-apoptosis mechanisms in human cells (fas and p53; bcl2) and in bacteria and viruses (p35, crmA) has allowed us to glimpse intracellular signaling. For a few specific situations, we can now trace a complete sequence controlling the survival of a cell. 11±23 Nevertheless, the clarity of these sequences is a bit meretricious. The inherent elegance and simplicity of these concepts (albeit not of the sequences±the simplicity is in the linearity of the scheme) belie at least two orders of complication. The first of these is that, in real life as opposed to a very controlled laboratory setting, signaling and transduction are often not linear but are dependent on very specific aspects of cell history and current state. The phase in which researchers expected a linear sequence of events, for instance from signal to transduction to gene activation to caspase activation, is over: The role of a given protein may be entirely contextual. Secondly, as the linear sequences are more precisely defined, it has become apparent that there are many variants to both the broad schemes and the more subtle details. Both of these limitations suggest that it is now time to bring the molecular biology to bear on the somewhat messier situations of apoptosis in vivo and in the situations of sedentary, large, highly differentiated post-mitotic cells, which rarely follow a conventional sequence of apoptosis. We need to accept the idea that the model of apoptosis based on cells of hematopoietic origin is an extremely important paradigm, but it is not universal.