An increasingly powerful approach for studying brain circuits relies on targeting genetically encoded sensors and effectors to specific cell types. However, current approaches for this are still limited in functionality and specificity. Here we utilize several intersectional strategies to generate multiple transgenic mouse lines expressing high levels of novel genetic tools with high specificity. We developed driver and double reporter mouse lines and viral vectors using the Cre/Flp and Cre/Dre double recombinase systems and established a new, retargetable genomic locus, TIGRE, which allowed the generation of a large set of Cre/tTA-dependent reporter lines expressing fluorescent proteins, genetically encoded calcium, voltage, or glutamate indicators, and optogenetic effectors, all at substantially higher levels than before. High functionality was shown in example mouse lines for GCaMP6, YCX2.60, VSFP Butterfly 1.2, and Jaws. These novel transgenic lines greatly expand the ability to monitor and manipulate neuronal activities with increased specificity. Display omitted •Evaluated multiple mouse transgenic intersectional strategies•Established TIGRE locus as a novel permissive docking site for transgene expression•Developed 21 new intersectional driver and reporter lines expressing novel tools•Demonstrated functionality of new voltage or calcium sensing or optogenetic lines Madisen et al. developed multiple intersectional transgenic mouse lines and AAVs for gene expression control with high specificity, in particular TIGRE locus-based high-level expression of calcium sensors GCaMP6 and YCX2.60, voltage sensor VSFP Butterfly 1.2, and optogenetic silencer Jaws.