In the 21st century, one of the major scientific challenges is to clarify and understand the significance of genetic variations in human health and diseases. Human genetic variations are usually correlated with the regular physiological function, so it has a tremendous boost for scientific researches and clinical testing in order to understand the effect of human genetic variations on human health. Related researches published after the Human Genome Project have enriched our knowledge of different human genetic variations and their evolutionary history and relationships. Many diseases are associated with clinical genetic variations which are prevalent in the genome. The phenotypic diversity, inherited diseases and susceptibility to complex diseases among individuals are considered to be caused by these genetic variations and non-genetic factors (e.g. environmental factors). Each genetic variation tends to have specific effects on human health. Most common genetic variations like SNPs, structural variations, chromosomal aberrations and genetic susceptibility are correlated with human health. The studies in this field will be greatly facilitated by deep understanding of the mechanisms by which mutations exert their dominant effects on human health. Moreover, understanding the effects of environmental factors and genetic variations including their interaction on human health are of the great challenging. Recent advances in technologies, especially the high-throughput sequencing technology and progressive development of related technologies, like next generation sequencing including whole genome sequencing, whole exome sequencing and targeted exome capture based sequencing have promoted scientific researches and clinical applications, which subsequently creates great improvement in the genetic diagnosis and treatment programs. Currently, the use of high-throughput technology on genetic testing has greatly expanded its scope from a single genetic disease screening to the detection of complex diseases and hereditary cancers. In present days, it is widely used in non-invasive prenatal testing, neonatal genetic testing, pedigree analysis and carrier screening. Simultaneously, technological improvement is also helping development in the field of pharmacogenomics and nutrigenomics. Genetic testing benefits research and clinical development greatly. Development and application of DNA sequencing technology has significantly promoted the study of human genetic variation and phenotypic differences relationship, and in particular to identify susceptible genes for complex diseases. Additionally, it has also contributed to studying the relationship between genetic variation and various drug ressistance or sensitivity, and the specific reactions of individuals to environmental factors. This article focuses on the impact and mechanism of different genetic variations of human health, and progress on scientific research and clinical applications led by technological advances, including the prevention and treatment of genetic diseases. At the same time, we also engage with future research trend of genetic variations, hoping to provide a reference for related research on human health.