Mitochondrial complex II (CII), also called succinate dehydrogenase (SDH), is a central purveyor of the reprogramming of metabolic and respiratory adaptation in response to various intrinsic and extrinsic stimuli and abnormalities. In this review we discuss recent findings regarding SDH biogenesis, which requires four known assembly factors, and modulation of its enzymatic activity by acetylation, succinylation, phosphorylation, and proteolysis. We further focus on the emerging role of both genetic and epigenetic aberrations leading to SDH dysfunction associated with various clinical manifestations. This review also covers the recent discovery of the role of SDH in inflammation-linked pathologies. Conceivably, SDH is a potential target for several hard-to-treat conditions, including cancer, that remains to be fully exploited. Recent research points to a major role of complex II (CII) in various aspects of cell biology, being at the crossroads of oxidative phosphorylation and the tricarboxylic acid cycle. CII therefore represents a branching point of two essential mitochondrial pathways. Dysfunction of succinate dehydrogenase (SDH) leads to accumulation of succinate, which is categorized as an oncometabolite and signaling molecule. CII is a major player in mitochondrial reactive oxygen species (ROS) generation and contributes ROS either directly or indirectly via reverse electron transfer (RET). Genetic mutations as well as epigenetic regulation of the SDHx genes are associated with several pathological conditions. Similarly, both metabolic and epigenetic malfunctions have emerged as the underlying molecular mechanisms of the pathologies. Several novel accessory proteins have been identified as crucial for the biogenesis of the SDH complex. They are referred to as assembly factors and emerging data show mutations in their genes to be linked to dysfunction of CII with clinical presentation. Modulation of SDH function under various metabolic conditions could be utilized as a promising therapeutic target.