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Anticancer drug discovery has historically been done empirically, screening for compounds that inhibit the growth of tumor cells in culture, or that are effective against implanted tumors in mice. This approach is analogous to the highly effective screens carried out in the 1950s and 1960s for antimicrobial agents and has had its successes – indeed, many of the anticancer drugs currently in clinical use were developed in this fashion. However, as our understanding of the molecular mechanisms underlying the development and growth of cancer cells has improved, new approaches to drug discovery have begun to build on this knowledge. The recognition that not all tumors arising in the same tissue are due to the same underlying defects calls for treatments regimes that will be tailored to these molecular alterations. The drug screen described in this chapter was initiated with the hypothesis that single gene changes that are often associated with particular hereditary and sporadic forms of cancer may serve as determinants of drug sensitivity [27]. In principle, there are two possible mechanisms by which a drug can be more toxic to a cell containing a particular genetic alteration. First, by a mechanism in which damage caused by the drug is normally repaired in a wild-type cell by a protein that has been deleted or altered in the mutant. An example of this is the sensitivity of mutants defective in recombinational repair of DNA double-strand breaks (DSBs) (e.g., yeast rad50 mutants) to agents that cause DSBs (e.g., the topoisomerase poison