MOTIVATION: A molecular interaction network can be viewed as a network in which genes with related functions are connected. Therefore, at a systems level, connections between individual genes in a molecular interaction network can be used to infer the collective functional linkages between biologically meaningful gene sets. RESULTS: We present the human interactome resource and the gene set linkage analysis (GSLA) tool for the functional interpretation of biologically meaningful gene sets observed in experiments. GSLA determines whether an observed gene set has significant functional linkages to established biological processes. When an observed gene set is not enriched by known biological processes, traditional enrichment-based interpretation methods cannot produce functional insights, but GSLA can still evaluate whether those genes work in concert to regulate specific biological processes, thereby suggesting the functional implications of the observed gene set. The quality of human interactome resource and the utility of GSLA are illustrated with multiple assessments. AVAILABILITY: http://www.cls.zju.edu.cn/hir/