Both experimental and clinical studies suggest that any potential treatment of polycystic kidney disease should start early and last for a long time to be effective, with unavoidable side reactions and considerable costs. The aim of the present study was to test how low-doses of Rapamycin (RAPA, 0.15 mg/Kg/4 days a week i.p.), Tolvaptan (TOLV, 0.005% in the diet) or AEZ131, a novel ERK inhibitor (AEZ, 30 mg/kg/thrice a week by gavage), alone and in association, affect the progression of polycystic renal disease in PCK rats. Rats were treated for 8 weeks, starting at 4-6 weeks of age. The efficacy of low-doses of such drugs in inhibiting their respective targets was confirmed by immunoblotting studies. Compared to control rats, RAPA determined a significant reduction in cyst volume density (CVD, -19% vs CON), numerically similar in TOLV treated rats (-18%, NS), whereas AEZ was not effective. RAPA+TOLV determined a significantly lower CVD (-49% vs CON), associated with a striking decrease in CREB phosphorylation, and similar data were detected in RAPA+AEZ rats (-42%), whereas the association TOLV+AEZ had virtually no effect. RAPA administration significantly lessened body weight gain, whereas TOLV determined mild increase in diuresis and a significant increase in cAMP urinary excretion. Histological data of tubular proliferation were in full agreement with the data of CVD. In conclusion, this study demonstrates that the association of low-doses of RAPA, TOLV and AEZ slows the progression of PKD with limited side effects, suggesting the use of combined therapies also in clinical trials.