Dysregulation of the myocardial extracellular matrix contributes to abnormal cardiac muscle function. Changes in the balance between matrix deposition and matrix degradation by matrix metalloproteinases (MMPs) can lead to cardiac fibrosis and dilation. In this review, we discuss the regulation of MMPs, their endogenous inhibitors (TIMPs) and collagen synthesis by inflammatory cytokines and reactive oxygen/nitrogen species (ROS/RNS). Inflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, and ROS activate mitogen-activated protein kinases and stress-responsive protein kinases in cardiac cells. In non-cardiac tissues, inflammatory cytokine activation of these kinases is redox sensitive, suggesting ROS may also be involved in cytokine signaling in the heart. Subsequent activation of transcription factors including AP-1, Ets, and nuclear factor κ-B leads to increased transcription of MMPs. ROS also directly activate MMPs post-translationally. In addition, inflammatory cytokines and ROS lead to decreased TIMP levels and collagen synthesis. Work in animal models suggests that inhibition of inflammatory cytokine or ROS signaling leads to less myocardial remodeling. Further study of the signaling of regulation of the cardiac extracellular matrix may lead to new approaches for the treatment of myocardial remodeling and failure.