Empirical evidence supporting the commonality of gene x gene interactions, coupled with frequent failure to replicate results from previous association studies, has prompted statisticians to develop methods to handle this important subject. Nonparametric methods have generated intense interest because of their capacity to handle high-dimensional data. Genome-wide association analysis of large-scale SNP data is challenging mathematically and computationally. In this paper, we describe major issues and questions arising from this challenge, along with methodological implications. Data reduction and pattern recognition methods seem to be the new frontiers in efforts to detect gene x gene interactions comprehensively. Currently, there is no single method that is recognized as the 'best' for detecting, characterizing, and interpreting gene x gene interactions. Instead, a combination of approaches with the aim of balancing their specific strengths may be the optimal approach to investigate gene x gene interactions in human data. Copyright © 2007 S. Karger AG.