Conditional genetic modifications are used to determine how individual molecules contribute to the function of defined neuronal circuits in the mouse brain. Among various techniques for these genetic modifications, the tetracycline transactivator and the Cre-loxP systems have proved to be most successful in recent years. Here we describe the basic principles, recent developments, and potential applications of these methodologies. We discuss their impact on the study of general brain function and their use for modeling different brain disorders.