Abstract <p>The discovery of pluripotent stem cells (PSCs) had a tremendous impact in various areas of biology, while the application of genetic approaches to these cells further expanded the repertoire of both fundamental and applied tasks addressed with the help of PSCs. For example, mouse embryonic stem cells (ESCs) have served as an indispensable tool in functional genetics, which allowed the researchers to define the biological role of thousands of mouse genes using gene knockout techniques. Subsequent discovery of human ESCs opened broad perspectives in tissue replacement therapy, while the discovery of induced pluripotent stem cells (iPSCs), which overcame several technical, immunological, and ethical issues associated with the derivation and clinical use of ESCs, has made the prospects even closer. The manuscript overviews some of the genetic approaches that, in combination with PSC technologies, can provide a new level of solution to a wide range of biomedical tasks.</p>