To address the challenge of identifying related members of a large family of genes, their variants and their patterns of expression, we have developed a novel technique known as targeted expressed gene display. Here, we demonstrate the general application of this technique by analyzing the SMAD genes and report that the loss of SMAD8 expression is associated with multiple types of cancers, including 31% of both breast and colon cancers. Epigenetic silencing of SMAD8 expression by DNA hypermethylation in cancers directly correlates with loss of SMAD8 expression. The SMAD8 alteration in a third of breast and colon cancers makes it a significant novel tumor marker as well as a potential therapeutic target. The utility of targeted expressed gene display for the analysis of highly homologous gene families as demonstrated by its application to the SMAD genes suggests that it is an efficient tool for the identification of novel members, simultaneous analysis of differential expression patterns, and initial discovery of alterations of expressed genes.