The locus coeruleus (LC) noradrenergic (NE) system is involved in a plethora of physiological and pathophysiological processes. Refining our understanding of LC function largely relies on selective transgene expression in molecularly defined cells, allowing targeted manipulation and readout of noradrenergic neurons. Here, we performed a side-by-side comparison of the most commonly used strategies to genetically access the LC, including different cre driver lines and promoter-mediated transgene expression. We report differences between these strategies in terms of transgene expression efficacy and molecular specificity. Notably, we found no behavioral alterations performing anxiety tests and memory tasks in cre-expressing mice of any mouse line as compared to wild-type littermates. Finally, to further ease the investigation of LC-NE function, we created a suite of constructs, including reporter proteins, calcium indicators, and optogenetic actuators whose expression is mediated by the previously described PRS×8 promoter. These constructs allow for monitoring and manipulation of LC-NE activity either in wild-type mice, or in combination with tissue-specific manipulations of different cre driver lines. The results of our study are crucial for the interpretation of results from previous experiments using the respective targeting strategies, as well as for the design of future studies.