OBJECTIVE Renin–angiotensin system (RAS) inhibitors decrease the urinary albumin to creat-inine ratio (UACR) but are ineffective in up to 40% of patients. We hypothesized that rotation through different drug classes overcomes RAS inhibitor resistance and tested this in a randomized crossover trial. RESEARCH DESIGN AND METHODS We assigned 26 adults with type 1 diabetes and 37 with type 2 diabetes and UACR between 30 and 500 mg/g and estimated glomerular filtration rate >45 mL/min/1.73 m² to 4-week treatment periods with telmisartan 80 mg, em-pagliflozin 10 mg, linagliptin 5 mg, and baricitinib 2 mg in random order, sepa-rated by 4-week washout periods. Each participant was then re-exposed for 4 weeks to the drug that induced that individual’s largest UACR reduction. Primary outcome was the difference in UACR response to the best-performing drug during the confirmation period versus UACR response to the other three drugs. RESULTS There was substantial variation in the best-performing drug. Telmisartan was best performing for 33 participants (52%), empagliflozin and linagliptin in 11 (17%), and baricitinib in 8 participants (13%). The individuals’ best-performing drug changed UACR from baseline during the first and confirmatory exposures by a mean of-39.6% (95% CI-44.8,-33.8; P < 0.001) and-22.4% (95% CI-29.7,-12.5; P < 0.001), respectively. The Pearson correlation for first versus confirmatory exposure was 0.39 (P = 0.017). The mean change in UACR with the other three drugs was +1.6% (95% CI-4.3%, 8.0%; P = 0.593 versus baseline; difference versus individu-als’ best-performing drug at confirmation, 30.9% [95% CI 18.0, 45.3]; P < 0.001). CONCLUSIONS We demonstrated a large and reproducible variation in participants’ responses to different UACR-lowering drug classes. These data support systematic rotation through different drug classes to overcome therapy resistance to RAS inhibition.