SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2 (SMYD2) is a protein methyltransferase that methylates histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) and diverse nonhistone proteins. SMYD2 activity is required for normal organismal development and the regulation of a series of pathophysiological processes. Since aberrant SMYD2 expression and its dysfunction are often closely related to multiple diseases, SMYD2 is a promising candidate for the treatment of these diseases, such as cardiovascular disease and cancer. Here, we present an overview of the complex biology of SMYD2 and its family members and their context-dependent nature. Then, we discuss the discovery, structure, inhibitors, roles, and molecular mechanisms of SMYD2 in distinct diseases, with a focus on cardiovascular disease and cancer.