Reverse genetics approaches have matured beyond the generation of simple loss-of-function (e.g., knockout mice) and gain-of-function (e.g., classical transgenic mice) models into technologies that provide conditional control over the expression of a gene of interest in a spatially and/or temporally regulated manner. Site-specific recombinases (SSRs), such as Cre recombinase and Flp recombinase, provide access to genetically defined cell populations enabling cell type-specific manipulation of gene activity or cellular function. The combination of SSR drivers with floxed/flrted genes, SSR-dependent reporters or other genetic tools (e.g., optogenetics, for further reading see Rein and Deussing, 2012) offers a plethora of possibilities to interrogate the function of genes and neural circuits. The latest establishment of site-specific nucleases (SSNs), such as transcription activator-like effector nucleases (TALENs), as well as RNA-guided nucleases (e.g. CRISPR/Cas system), are currently implemented to expand the engineering tools (for further reading see Deussing 2013).