Cells respond to extracellular stimuli by activating signal transduction pathways, which culminate in changes in gene expression. The particular genetic program activated determines, in large part, the response of the cell (eg, growth versus growth arrest versus apoptosis; differentiation versus dedifferentiation). A critical component of eukaryotic signal transduction is the activation of protein kinases, which phosphorylate a host of cellular substrates, including transcription factors controlling the induction of various genes. For example, the Ras/ERK-1 and ERK-2 (or MAP kinase) pathway transduces critical components of the growth factor-induced mitogenic response to the nucleus. Expression of inactive or interfering mutants of components of the pathway disrupts, and expression of constitutively active mutants activates, mitogenesis.'Recently, protein serine/threonine kinases related to ERK-1 and-2 have been identified; these kinases transduce signals to the nucleus not in response to growth factors and other mitogens but in response to cellular stresses such as inflammatory cytokines (IL-1/3 and TNF-a), ischemia, reversible ATP depletion, heat shock, endotoxin, and genotoxic stress. These kinases, called the SAPKs2 or, alternatively, c-Jun N-terminal (aminoterminal) kinases (JNKs, named after one of their physiological substrates), 3 and p38, 4 likely play critical roles in the genetic response of many components of the cardiovascular system to disease processes (Table). In this review, we will discuss these stress-activated kinases, how they are regulated, and the evidence suggesting roles they may play in cardiovascular disease.