ESTs are a tremendous resource for determining the exon-intron structures of genes, but even extensive EST sequencing tends to leave many exons and genes untouched. Gene prediction systems based exclusively on EST alignments miss these exons and genes, leading to poor sensitivity. De novo gene prediction systems, which ignore ESTs in favor of genomic sequence, can predict such untouched exons, but they are less accurate when predicting exons to which ESTs align. TWINSCAN is the most accurate de novo gene finder available for nematodes and N-SCAN is the most accurate for mammals, as measured by exact CDS gene prediction and exact exon prediction.