The tautomerism and protonation of 7-aminopyrazolopyrimidine in the gas phase are studied by means of ab initio methods. The effect of the solvent on the tautomerization and protonation processes is accounted for by using several high-level techniques including molecular dynamics-free energy perturbation (MD-FEP), an optimized ab initio self-consistent reaction field (SCRF) method, and two different semiempirical SCRF methods. The results not only provide a complete picture of the tautomerism and protonation of 7-aminopyrazolopyrimidine but also allow us to compare different "state-of-the-art" techniques to represent solvation effects. The biochemical and pharmacological importance of the tautomerism and protonation of 7-aminopyrazolopyrimidine is discussed.