<p>Multiple peaking in pharmacokinetics refers to the occurrence of two or more peaks of drug plasma concentrations following a single dose administration. It complicates interpretation of pharmacokinetics parameters and influences clinical decision-making regarding drug efficacy and bioequivalence. This review re-examines and extends an earlier seminal review on the physicochemical and formulation-related causes and physiological mechanisms of multiple peaking. In addition to the previously discussed mechanisms, factors such as lymphatic drug uptake, enterogastric recycling, hepatoenteric recycling, dual absorption pathways, overdose scenarios, and pharmacobezoar formation have also been identified as contributors to the multiple peaking phenomenon. Furthermore, the role of specialized formulations, particularly pulsatile drug delivery systems (PDDS), has been explored in relation to their impact on this complex pharmacokinetics behavior. Moreover, this review highlights advanced modeling tools, namely physiologically based pharmacokinetic modeling (PBPK), illustrating how they can be applied to decipher complex absorption profiles, and highlights bioequivalence considerations for products exhibiting multiple peaks, such as partial area under the curve (pAUC). Improved identification and modeling of this phenomenon is critical to optimizing drug development, therapeutic monitoring, precision dosing, and regulatory decision-making.</p>