Gene-set analysis evaluates the expression of biological pathways, or a priori defined gene sets, rather than that of individual genes, in association with a binary phenotype, and is of great biologic interest in many DNA microarray studies. Gene Set Enrichment Analysis (GSEA) has been applied widely as a tool for gene-set analyses. We describe here some critical problems with GSEA and propose an alternative method by extending the individual-gene analysis method, Significance Analysis of Microarray (SAM), to gene-set analyses (SAM-GS).