A dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation has been identified. Calcium/calmodulin-dependent protein kinase II (CaMKII) is typically activated by calcium and calmodulin, but recent evidence shows that it can also be activated by oxidative conditions. This study demonstrates that oxidation of methionine residues in the regulatory domain of CaMKII sustains its activity in the absence of calcium and calmodulin. Angiotensin II (AngII)-induced oxidation activates CaMKII, leading to apoptosis in cardiomyocytes both in vitro and in vivo. Methionine sulfoxide reductase A (Msra) reverses this oxidation, and Msra-deficient mice show increased CaMKII oxidation, apoptosis, and impaired cardiac function after myocardial infarction. These findings highlight the importance of oxidation-dependent CaMKII activation in AngII and ischemic myocardial apoptosis. CaMKII is a multifunctional enzyme that couples increases in intracellular calcium to various cellular responses, including ion channel activation, gene transcription, and apoptosis. It is activated by enhanced intracellular calcium from β-adrenergic receptor stimulation. Excessive β-adrenergic receptor stimulation causes apoptosis through a calcium-calmodulin and caspase-3-dependent pathway. CaMKII is composed of subunits with three key domains: the association domain, the regulatory domain, and the catalytic domain. Under resting conditions, CaMKII is inactive, but upon binding calcium and calmodulin, a conformational change relieves the autoinhibitory effect of the regulatory domain on the kinase domain, activating the enzyme. In the presence of calcium and calmodulin, CaMKII undergoes intersubunit autophosphorylation at T287, resulting in calcium and calmodulin-independent activity. CaMKII activity may also increase in pro-oxidant cellular environments, suggesting that CaMKII has broader functionality than originally envisioned. Based on the previously recognized structure-activity response of CaMKII to T287 phosphorylation, it was hypothesized that oxidation directly modifies the autoinhibitory motif to confer calcium and calmodulin-independent CaMKII activity by a mechanism analogous to autophosphorylation. The study identified a direct molecular mechanism for reactive oxygen species (ROS)-dependent, calcium-independent CaMKII activation by modification of M281/282. These findings show that direct activation of CaMKII by ROS engenders calcium-autonomous activity, a clear but previously unrecognized molecular mechanism by which CaMKII can integrate calcium and ROS signals. Elevated levels of ROS have been measured and contribute to adverse outcomes after myocardial infarction and in models of heart failure. Angiotensin II also increases ROS in the heart, while AngII antagonist drugs are a mainstay for reducing mortality in patients with structural heart disease. The study hypothesized that CaMKIIA dynamic pathway for calcium-independent activation of CaMKII by methionine oxidation has been identified. Calcium/calmodulin-dependent protein kinase II (CaMKII) is typically activated by calcium and calmodulin, but recent evidence shows that it can also be activated by oxidative conditions. This study demonstrates that oxidation of methionine residues in the regulatory domain of CaMKII sustains its activity in the absence of calcium and calmodulin. Angiotensin II (AngII)-induced oxidation activates CaMKII, leading to apoptosis in cardiomyocytes both in vitro and in vivo. Methionine sulfoxide reductase A (Msra) reverses this oxidation, and Msra-deficient mice show increased CaMKII oxidation, apoptosis, and impaired cardiac function after myocardial infarction. These findings highlight the importance of oxidation-dependent CaMKII activation in AngII and ischemic myocardial apoptosis. CaMKII is a multifunctional enzyme that couples increases in intracellular calcium to various cellular responses, including ion channel activation, gene transcription, and apoptosis. It is activated by enhanced intracellular calcium from β-adrenergic receptor stimulation. Excessive β-adrenergic receptor stimulation causes apoptosis through a calcium-calmodulin and caspase-3-dependent pathway. CaMKII is composed of subunits with three key domains: the association domain, the regulatory domain, and the catalytic domain. Under resting conditions, CaMKII is inactive, but upon binding calcium and calmodulin, a conformational change relieves the autoinhibitory effect of the regulatory domain on the kinase domain, activating the enzyme. In the presence of calcium and calmodulin, CaMKII undergoes intersubunit autophosphorylation at T287, resulting in calcium and calmodulin-independent activity. CaMKII activity may also increase in pro-oxidant cellular environments, suggesting that CaMKII has broader functionality than originally envisioned. Based on the previously recognized structure-activity response of CaMKII to T287 phosphorylation, it was hypothesized that oxidation directly modifies the autoinhibitory motif to confer calcium and calmodulin-independent CaMKII activity by a mechanism analogous to autophosphorylation. The study identified a direct molecular mechanism for reactive oxygen species (ROS)-dependent, calcium-independent CaMKII activation by modification of M281/282. These findings show that direct activation of CaMKII by ROS engenders calcium-autonomous activity, a clear but previously unrecognized molecular mechanism by which CaMKII can integrate calcium and ROS signals. Elevated levels of ROS have been measured and contribute to adverse outcomes after myocardial infarction and in models of heart failure. Angiotensin II also increases ROS in the heart, while AngII antagonist drugs are a mainstay for reducing mortality in patients with structural heart disease. The study hypothesized that CaMKII