Over the last decade, genome-wide association studies led to major advances in identifying human genetic variants associated with infectious disease susceptibility. On the pathogen side, comparable methods are now applied to identify disease-modulating pathogen variants. As host and pathogen variants jointly determine disease outcomes, the most recent development has been to explore simultaneously host and pathogen genomes, through so-called genome-to-genome studies. In this review, we provide some background on the development of genome-to-genome analysis and we detail the first wave of studies in this emerging field, which focused on patients chronically infected with HIV and hepatitis C virus. We also discuss the need for novel statistical methods to better tackle the issues of population stratification and multiple testing. Finally, we speculate on future research areas where genome-to-genome analysis may prove to be particularly effective.