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Purine and pyrimidine nucleotides are essential for a vast number of biological processes such as RNA and DNA synthesis and as a component of high-energy nucleotides, e.g., ATP. Polygenic and monogenic diseases are associated with altered purine and pyrimidine metabolism; thus, the genes associated with gout have only minor effects on serum urate levels and the combination of such genetic factors as well as environmental factors cause the disease. Recent genome-wide association studies have identified such genes many of which code for transporters in renal tubules and related proteins. Monogenic diseases include enzyme abnormalities in the purine and pyrimidine pathways. Although most of the abnormalities were found by the candidate gene approach, Miller syndrome was found to be caused by the mutations in dihydroorotate dehydrogenase gene (DHODH) by whole exome sequencing. To date, more than 30 defects associated with purine and pyrimidine metabolism have been described. Inherited disorders of purine and pyrimidine metabolism have a wide variety of clinical presentations including anemia, immunodeficiency, renal stones, convulsions, mental retardation, autism, growth retardation, and serious adverse reactions to medication. For immunodeficiency caused by adenosine deaminase deficiency, enzyme replacement therapy and somatic gene therapy targeted at hematopoietic stem cells have been successful.