Sequence tag analysis using serial analysis of gene expression (SAGE) is a powerful strategy for the quantitative analysis of gene expression in human genetic disorders. SAGE facilitates the measurement of mRNA transcripts and generates a non-biased gene expression profile of normal and pathological disease tissue. In addition, the SAGE technique has the capacity of detecting the expression of novel transcripts allowing for the identification of previously uncharacterised genes, thus providing a unique advantage over the traditional microarray-based approach for expression profiling. The technique has been successful in providing pathological gene expression profiles in a number of common genetic disorders including diabetes, cardiovascular disease, Parkinson disease and Down syndrome. When combined with next generation sequencing platforms, SAGE has the potential to become a more powerful and sensitive technique making it more amenable for diagnostic use. This review will therefore discuss the application of SAGE to several common genetic disorders and will further evaluate its potential use in diagnosing human genetic disease.