The selection and optimization of drug leads is largely driven by equilibrium parameters such as IC50 values. However, this approach does not account for the time-dependence of drug-target interactions which is important given that drug and target concentrations fluctuate in the human body. A fundamental understanding of drug-target binding kinetics is particularly important when the formation and breakdown of the drug-target complex is slow compared to the rate of drug elimination and becomes critical when dealing with covalent drugs where the drug is irreversibly bound to the target. The parameters that define covalent inhibition, specifically kinact and KI, can be determined by quantifying target binding as a function of drug concentration and time. However, such assays are difficult to implement in early stages of drug discovery. Here, we review practical approaches to quantify irreversible inhibition including progress-curve kinetics, multi-timepoint IC50 fitting (EPIC) for scalable library triage, intact- and peptide-level mass spectrometry to confirm adducts and sites, label-free biophysics (SPR, NMR) for orthogonal validation, and washout/jump-dilution experiments to diagnose reversibility and measure residence time (τ). We then describe the translation of these microscopic rates to pharmacology through three system determinants: protein turnover, target vulnerability, and pharmacokinetics using case studies from BTK, JAK3, KRASG12C, and EGFR to illustrate how aligning chemistry with context yields durable efficacy. Finally, we propose reporting standards (IC50 with incubation time; kinact/KI; τ; turnover-driven occupancy) and a kinetics-first design paradigm to replace static potency with mechanism-anchored optimization of covalent inhibitors.