β2-Adrenoceptor (β2-AR) agonists are widely used as bronchodilators. The emerge of ultralong acting β2-agonists is an important breakthrough in pulmonary medicine. In this review, we will provide mechanistic insights into the application of β2-agonists in asthma, chronic obstructive pulmonary disease (COPD), and heart failure (HF). Recent studies in β-AR signal transduction have revealed opposing functions of the β1-AR and the β2-AR on cardiomyocyte survival. Thus, β2-agonists and β-blockers in combination may represent a novel strategy for HF management. Allosteric modulation and biased agonism at the β2-AR also provide a theoretical basis for developing drugs with novel mechanisms of action and pharmacological profiles. Overlap of COPD and HF presents a substantial clinical challenge but also a unique opportunity for evaluation of the cardiovascular safety of β2-agonists. Further basic and clinical research along these lines can help us develop better drugs and innovative strategies for the management of these difficult-to-treat diseases.