Genome-wide association studies (GWAS) have made significant strides in identifying genetic loci associated with complex traits and diseases. However, most of these loci lie outside of coding regions and their molecular mechanisms remain largely unexplained. Mapping expression quantitative trait loci (eQTLs) has emerged as a key tool for uncovering regulatory mechanisms of non-coding loci by linking genetic variants to gene expression changes. Despite the progress made by large-scale eQTL studies, many GWAS loci are not explained by existing eQTL data from steady-state healthy samples. In this dissertation, I explore context-dependent genetic effects that are often overlooked in conventional eQTL studies. I leverage two different models to investigate how genetic variants influence gene expression in response to environmental perturbations and their potential for enhancing the interpretation of disease-associated loci. In Chapter II, I investigate genetic regulatory effects in response to a high-cholesterol, high-fat diet in baboons. By analyzing RNA-sequencing data from metabolically relevant tissues of 99 baboons, I identified hundreds of diet-responsive eQTLs. These diet-responsive eQTLs exhibit distinct signatures of regulatory complexity, evolutionary constraint, and functional enrichment that distinguish them from standard, steady-state eQTLs. The human orthologs associated with diet-responsive eQTLs are enriched for GWAS genes associated with human metabolic traits, suggesting that context-responsive eQTLs with more complex regulatory effects are likely to explain GWAS hits that do not seem to overlap with standard eQTLs. To more efficiently explore gene-environment (GxE) interactions across diverse cellular contexts, I leverage heterogeneous differentiating cultures (HDCs) as a flexible and scalable system. In Chapter III, I perturbed a broad array cell types from 51 individuals with chemical exposures: ethanol, caffeine, and nicotine. With single-cell RNA-sequencing data from 1.4 million cells, I identified hundreds of dynamic eQTLs that regulate molecular responses to perturbation across multiple cellular contexts. Similar to diet-responsive eQTLs in baboons, response eQTLs in HDCs also show different properties from standard eQTLs. They are enriched in distal enhancers and are linked to genes that experienced strong selective constraint, involve in complex regulatory landscapes and diverse biological functions. Furthermore, response eQTLs are more likely than standard eQTLs to colocalize with GWAS signals for complex traits, suggesting their critical role in mediating the effects of disease-associated loci. Together, this work demonstrates that context-responsive eQTLs—whether induced by dietary changes in baboons or chemical exposures in HDCs—exhibit unique characteristics that align more closely with disease-associated loci from GWAS. The findings from this dissertation highlight the value of considering GxE interactions in uncovering the functional relevance of non-coding genetic variants, particularly those that fail to exhibit regulatory potential under steady-state conditions. By expanding the scope of eQTL studies to include diverse environmental and biological contexts, we will identify more context-dependent and functionally relevant regulatory loci, thereby moving closer to translating GWAS findings into actionable insights for human health.