The high lateral resolution and sensitivity of the NanoSIMS 50 and 50L series of dynamic SIMS instruments have enabled numerous scientific advances over the past 25 years. Here, we report on the NanoSIMS-HR, the first major upgrade to the series, and analytical tests in a suite of sample types, including an aluminum sample containing silicon crystals, microalgae, and plant roots colonized with a symbiotic fungus. Significant improvements have been made in the Cs+ ion source, high voltage (HV) control, stage reproducibility, and other aspects of the instrument that affect performance. The modified design of the NanoSIMS-HR thermal-ionization Cs+ source enables a 5 pA primary ion beam to be focused into a 100 nm spot, a ∼2.5-fold increase compared to Cs+ sources on previous instruments (∼2 pA at 100 nm). The brightness of the new Cs+ source enables an ultimate lateral resolution as high as 30 nm and improved detection limits for a given analysis area. Sample stage movement accuracy is higher than 500 nm, enabling many-fold higher throughput automated analyses. With the new HV control, the primary ion beam impact energy can be reduced from 16 to 2 keV, which enables higher depth resolution during depth profiling (a 2-fold improvement), albeit with a 5-fold decrease in lateral resolution. In the NanoSIMS-HR, the secondary ion column and detection system are identical to those used in the previous series, and the isotopic analysis performance is as precise as in previous NanoSIMS instruments.