Small effect sizes, common-disease/common-variant versus rare variant influences, biased single nucleotide polymorphism ascertainment and low linkage disequilibrium have recently been discussed as impediments to association studies. Such a focus on the individual factors that highlight their maximum potential effect (whether positive or deleterious) is often optimistic as, in practice, they do not operate in isolation. Instead, they work jointly to generate the disease gene architecture and to determine the ability of a study to discover it. Here, we consider how the effect size of the susceptibility locus, the frequency of the disease allele(s), the frequency of the marker allele(s) that are correlated with the disease allele(s) and the extent of linkage disequilibrium together influence genetic association studies.