There is a continued desire in biomedical research to reduce the number and duration of design cycles required to optimize lead compounds into high-quality chemical probes or safe and efficacious drug candidates. The insightful application of impactful molecular design elements is one approach toward achieving this goal. The replacement of a CH group with a N atom in aromatic and heteroaromatic ring systems can have many important effects on molecular and physicochemical properties and intra- and intermolecular interactions that can translate to improved pharmacological profiles. In this Perspective, the "necessary nitrogen atom" is shown to be a versatile high-impact design element for multiparameter optimization, wherein ≥10-, 100-, or 1000-fold improvement in a variety of key pharmacological parameters can be realized.