The development of site-selective functionalization of N-heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination of pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4-aminopyridines, a versatile pharmacophore in medicinal chemistry. Herein, we report a reaction manifold for the C4-selective amination of pyridines by employing nucleophilic substitution of hydrogen (SNH). Through 4-pyridyl pyridinium salt intermediates, 4-aminopyridine products are obtained in reaction with aqueous ammonia without intermediate isolation. The notable regioselectivity was achieved by the electronic tuning of the external pyridine reagents along with the maximization of polarizability in the proton elimination stage. Further mechanistic investigations provided a guiding principle for the selective C-H pyridination of additional N-heteroarenes, presenting a strategic avenue for installation of diverse functional groups. Tailored pyridine reagents undergo nucleophilic substitution of hydrogen (SNH) reactions with activated pyridines to afford pyridyl pyridinium salts in C4-selectivity. These salts can be in situ converted to 4-aminopyridines by aqueous ammonia or utilized as synthetic linchpins for general pyridine C4-functionalization. The elucidation of the selectivity principles has further guided the C4-selective functionalization of other (di)azines.+ image