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The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions.This article is part of the Special Issue entitled ‘Channelopathies.’The genetic channelopathies are a broad group of diseases which affect multiple organ systems.Most genetic channelopathies demonstrate marked phenotypic pleiotropy.Mechanisms underpinning phenotypic pleiotropy include functional effects of mutations, modifying genes, and environmental influences.Precision medicine treatment of channelopathies has shown early promise, but faces a number of challenges.