Under most conditions, 2,4-dihalopyrimidines undergo substitution reactions at C4. Here we report that Pd(II) precatalysts supported by bulky N-heterocyclic carbene ligands uniquely effect C2-selective cross-coupling of 2,4-dichloropyrimidine with thiols. The regioselectivity of this reaction stands in stark contrast to ∼1500 previously reported Pd-catalyzed cross-couplings that favor C4 in the absence of other substituents on the pyrimidine ring. Selectivity in the catalytic system reported herein is extremely sensitive to the structure of the Pd(II) precatalyst, largely due to competing C4-selective nucleophilic aromatic substitution. C2-selectivity is high with most 1° thiols and thiophenols, and a range of substituted dichloropyrimidines can be used. The atypical selectivity of this transformation may facilitate diversity-oriented synthesis, as demonstrated for derivatives of an antiviral agent. Under these conditions, C2─Cl cleavage may not take place through a typical oxidative addition pathway.