Normal human cells replicate their DNA with exceptional accuracy. During every division cycle, each daughter cell receives a full and accurate complement of genetic information. It has been estimated that approximately one error occurs during DNA replication for each 109 to 1010 nucleotides polymerized. Stem cells, the cells that are progenitors of cancer, may replicate their genes even more accurately. In contrast, the malignant cells that constitute a tumor are markedly heterogeneous and exhibit multiple chromosomal abnormalities and alterations in the nucleotide sequence of DNA. To account for the disparity between the rarity of mutations in normal cells and the large numbers of mutations present in cancer, we initially hypothesized that during tumor progression, cancer cells must exhibit a mutator phenotype. In this perspective, we summarize the evidence supporting a mutator phenotype in human cancer, analyze recent measurements of mutations in human cancer, consider the timing for the expression of a mutator phenotype, and focus on the important consequences of large numbers of random mutations in human tumors. Environ. Mol. Mutagen., 2005. © 2005 Wiley-Liss, Inc.