Procedural sedation in patients with congenital heart disease (CHD) is associated with significant morbidity and mortality. It is vital for the practitioner to fully understand the complexity of lesions, their hemodynamics, and the impact of medications commonly used for procedural sedation on the stability of systemic vascular resistance and pulmonary flow. According to the literature, we explain the interaction of the systemic vascular resistance and pulmonary flow in such lesions and divide them into five categories outlined in this article: (1) CHDs with left-to-right shunt with normal pulmonary arterial pressure and resistance, (2) CHD with left-to-right shunt and moderate to severe elevation of pulmonary arterial pressure with near-normal pulmonary vascular resistance, (3) CHD with pulmonary flow dependent on systemic vascular resistance, (4) patients with congenital coronary stenosis and coronary anomalies, and 5) aortic obstructive lesions.