Recent genetic research has led to the identification of a significant number of genes with a major influence on epilepsy, but the genes identified so far affect risk in a very small proportion of patients – primarily those from families consistent with Mendelian modes of inheritance. Identification of genes in the genetically complex epilepsies, affecting the vast majority of patients, is a major challenge for the next decade. In this chapter we review the types of genetic mechanisms that could be involved, study designs used to identify them, and the results of recent family and genetic studies of the complex epilepsies. Given the clinical and etiologic heterogeneity of the epilepsies, understanding the relationship of genotype to phenotype is an extremely important goal for research aimed at gene identification. We review two research designs aimed at clarifying “phenotype definition” in the epilepsies: familial aggregation studies and family concordance studies. The results of these analyses may clarify the extent to which the different clinically-defined epilepsy syndromes differ with respect to their genetic contributions, providing guidance about how best to define epilepsy subgroups likely to share susceptibility genes. Over the last two decades, more than 20 genes with a major effect on risk for human epilepsy have been identified, providing important clues to pathogenic mechanisms and enabling some patients to discover the cause of their disorder.1 However, the genes identified so far affect risk in a very small proportion of patients – primarily those from families consistent with Mendelian modes of inheritance. Most epilepsies occur in the absence of a significant family history, and identifying and characterizing the genetic mechanisms in these “complex epilepsies” is a major challenge for the next decade.2 Here we discuss the meaning of “complex inheritance” as it applies to epilepsy, findings from current research, and approaches likely to be advantageous for gene identification in these forms of epilepsy.