While there is evidence that host genetics plays a role in susceptibility and subsequent sequelae of sexually transmitted infections (STIs), association findings have been inconsistent in deciphering the causal genes or biological pathways involved in the different life cycle and pathogenesis of infectious microbes. The lack of replication and validation studies from genome-wide association studies in general and specifically with infectious diseases, including STIs, is a continuing problem that limits the utility of these studies. Cohort heterogeneity, sample size, and confounding by population stratification due to differences in genetic polymorphisms in different ethnic groups are the usual explanations. However, in the context of genetic epidemiology studies of infectious disease, apart from the involvement of at least two genomes (the host and the pathogen), local environmental factors in the host shared by concomitant infections are often not examined. Different infectious microbes contribute to the shared local microenvironment, and the immune response can be favorable or unfavorable to different microbes individually and concomitantly at various levels. The balance of each infection relative to the other concomitant infections is a major confounder that has been under-studied. Thus, host genetic studies examining only one pathogen can yield inconsistent associations. This warrants a new paradigm that uses an ecological network-based study design and analysis tools. Defining the role of genetics in concomitant infection is likely to provide insight into pathogenic and protective mechanisms and to identify interdependent molecular targets for prophylactic and therapeutic interventions to multiple co-infections.