Review β-blockers play a central role in the treatment of the various main cardiovascular diseases, including hypertension, coronary artery disease and systolic heart failure. As a therapeutic class, β-blockers form a heterogeneous family that differs in their pharmacokinetic (PK) and pharmacodynamic (PD) properties, highlighting the relevance of the extensive evaluation of PK/PD properties of these agents in order to optimize the outcomes of the treatment of cardiovascular diseases. Preclinical and clinical studies using PK/PD models have been able to identify different factors associated with cardiovascular response of β-blockers, including age, pharmaceutical formulation and genetic polymorphism, among others. PK/PD modeling of β-blockers can also be attractive for the early detection of poor responders and the optimization of dose regimen in their different indications.