Postural tachycardia syndrome (POTS) is the combination of an exaggerated heart rate response to standing, in association with symptoms of lightheadedness or pre-syncope that improve when recumbent. The condition is often associated with fatigue and brain fog, resulting in significant disruptions at a critical time of diagnosis in adolescence and young adulthood. The heterogeneity of the underlying pathophysiology and the variable response to therapeutic interventions make management of this condition challenging for both patients and physicians alike. Here, we aim to review the factors and mechanisms that may contribute to the symptoms and signs of POTS and to present our perspectives on the clinical approach toward the diagnosis and management of this complex syndrome.