Accurate and detailed understanding of the effects of variants in the coding and noncoding regions of the genome is the next big challenge in the new genomic era of personalized medicine, especially to tackle newer findings of genetic and phenotypic heterogeneity of diseases. This is necessary to resolve the gene-variant-disease relationship, the pathogenic variant spectrum of genes, pathogenic variants with variable clinical consequences, and multiloci diseases. In turn, this will facilitate patient recruitment for relevant clinical trials. In this review, we describe the trends in research at the intersection of basic and clinical genomics aiming to (a) overcome molecular diagnostic challenges and increase the clinical utility of next-generation sequencing (NGS) platforms, (b) elucidate variants associated with disease, (c) determine overall genomic complexity including epistasis, complex inheritance patterns such as "synergistic heterozygosity," digenic/multigenic inheritance, modifier effect, and rare variant load. We describe the newly emerging field of integrated functional genomics, in vivo or in vitro large-scale functional approaches, statistical bioinformatics algorithms that support NGS genomics data to interpret variants for timely clinical diagnostics and disease management. Thus, facilitating the discovery of new therapeutic or biomarker options, and their roles in the future of personalized medicine.