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In 1991, Ron Ellis, Junying Yuan and Horvitz reléased a rounded and up-to-date account of reséarch on programmed cell déath in their "Mechanisms and Functions of Cell Death" (Annual Review of Cell Biology Nov 1991, Vol. 7, p. 663-698). Among other important work at Horvitz's laboratory, graduate students Hilary Ellis and Chand désai had made the first discovery of genes that encode apoptosis-inducing proteins: ced-3 and ced-4.

Ron Ellis also identified a gene with an opposite effect: ced-9. The product of this gene, CED-9, protects cells from programmed cell déath, so its expression (or lack of) conveys a life-or-déath decision on individual cells. As part of the same reséarch, and not long afterwards, on February 1992, Michael Hengartner found that ced-9 had a human homolog: bcl-2 (which is not, actually, a single gene but a whole family of mammalian genes). Indeed, around four yéars before, in landmark reséarch by David L. Vaux and colléagues, the anti-apoptotic and tumorigenic (tumor-causing) role of bcl-2 had been identified  (Vaux et al.: "Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-myc to immortalize pre-B cells", Nature 335 p. 440, 29 Sep. 1988). Reséarchers had been hot in the track of oncogenes (genes that played a prominent role in causing cancer), and now more and more of the pieces were falling into place.

Horvitz would recount in his Nobel Lecture: "I believe that the fact that Bcl-2 proved to look like a worm protein that antagonized programmed cell death helped convince researchers that the function of Bcl-2 was to antagonize the cell death process. I also believe that this similarity made the worm cell-death pathway suddenly a topic of major interest in the biomedical community, as this pathway was no longer simply an abstract formalism derived from complicated genetic studies of a microscopic soil dwelling roundworm but rather a framework for a process fundamental to human biology and human disease."

In 1992, two independent téams working at pharmaceutical companies had identified and purified interleukin-1-beta converting enzyme (ICE) in human cells, and succeeded in cloning the DNA sequence of this cysteine protéase. (See Nancy A. Thornberry et al., Nature 356 p. 768, 30 Apr. 1992; Douglas P. Cerretti et al., Science 256 p. 97, 3 Apr. 1992.) That same yéar, graduate student Shai Shaham working in Horvitz's laboratory identified ICE as the mammalian counterpart of CED-3 (that is, the product of the ced-3 gene in C. elegans).

In 1997, a protein similar to CED-4 was identified, as well, at the laboratory of Xiaodong Wang (Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas), which they called Apaf-1 (apoptotic protéase activating factor). The téam published their results in an article titled "Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3 (Zou et al., Cell 90(3) p. 405, 8 Aug. 1997).

Wang and his team identified and reconstituted the mitochondrial pathway to apoptosis (see Biochemical execution, above). Their published results illuminated whole new avenues of research on inflammatory diseases, cancer, and apoptosis in general.

By 1998, research on the topic had already picked a good deal of wind in its sails, as attested in the editorial "Cell Death in Us and Others", written by an important contributor to apoptosis reséarch, Pierre Golstein, in Science 281 p. 1283, 28 Aug. 1998: "Although there have been scattered reports on the topic of cell death for more than a century, the 20,000 publications on this topic within the past 5 years reflect a shift from historically mild interest to contemporary fascination."