The identification of cancer-susceptibility genes has revolutionized our understanding of cancer. Most of these genes were originally thought to control cellular proliferation directly, acting as' gatekeepers'. But in the last few years it has become clear that genes that maintain the integrity of the genome ('caretakers') may be even more frequent causes of inherited predispositions to cancer. Now, on pages 772 and 804 of this issue, Milner et al. 1 and Sharan et al. 2 illuminate entirely different properties of the breast-cancer-susceptibility genes BRCAJ and BRCA2, emphasizing the important conceptual and practical differences between gatekeeper and caretaker genes. Defining the biochemical and biological functions that are relevant to tumorigenesis can be particularly vexing with genes like BRCAJ and BRCA2, which are large and probably have many functional domains. Although BRCAl and BRCA2 are unrelated at the sequence level, recent research has revealed intriguing similarities between them. First, both contain a region that can act as a transcriptional-activation domain when it is fused to a DNA-binding domain from another gene1'3. 4. Naturally occurring mutations found in both BRCAl and BRCA2 in breast-cancer families can compromise this transcriptional activation. As transcription factors are often found among the gatekeeper class of cancer-susceptibility genes, this property indicates that BRCAl and BRCA2 may directly control cellular proliferation. Moreover, BRCAl can inhibit the growth of cells in which it is overexpressed5, and there is a link between an inhibitor of cell-cycle-dependent kinases and the BRCAl protein6• However, each of these functional attributes ofBRCA is of uncertain specificity. The second similarity is that both BRCA I and BRCA2 bind to RadSI, a protein that is involved in maintaining the integrity of the