Oligonucleotides are small molecules 8–50 nucleotides in length that bind via Watson-Crick base pairing to enhance or repress the expression of target RNA. The use of oligonucleotides to manipulate gene expression in the kidney could be a valuable tool to further understand kidney pathophysiology and can serve as an important complement to genetic studies. This chapter serves as a primer on the use of oligonucleotides in the kidney. We provide an overview of the various ways that oligonucleotides can manipulate gene expression. In addition, we describe the advancements in the development of oligonucleotides for laboratory and clinical use. Finally, instruction is provided on the design and implementation of oligonucleotides for in vitro and in vivo laboratory studies.