Heightened cardiac adrenergic nervous system (ANS) activity and progression of left ventricular (LV) remodeling are temporally related in patients with systolic heart failure. Whether cardiac ANS activation directly contributes to or merely accompanies LV remodeling remains an unresolved issue. Human and experimental data that directly link cardiac ANS activation to LV remodeling and worsening heart failure are first reviewed, including cardiac norepinephrine spillover. Alterations of beta adrenergic receptor signaling pathways are then addressed with emphasis on the mechanisms that may mediate the beneficial effect of beta adrenergic receptor blockade on LV remodeling. Lastly, alternative approaches to beta adrenergic receptor blockade for lessening cardiac ANS activation and reversing cardiac ANS-induced LV remodeling are discussed. A large body of work now links LV remodeling to cardiac ANS activation. However, the precise mechanisms that link cardiac ANS activation to LV remodeling are still to be fully understood. Fully understanding of these mechanisms may uncover new therapeutic approaches.