Heart failure resulting in hospitalization represents a significant and growing health care burden. Heterogeneity characterizes this group in terms of mode of presentation, pathophysiology, and prognosis. The vast majority of patients symptomatically improve during hospitalization; however, their early post-discharge rehospitalization and mortality rates continue to be high. Worsening signs and symptoms, neurohormonal, and renal abnormalities occurring soon after discharge may contribute to these high post-discharge event rates. Currently available assessment modalities combined with recent advances in cardiovascular therapies provide present-day opportunities to improve post-discharge outcomes. Further investigation into pathophysiologic targets and novel approaches to clinical trial design are needed. Improving post-discharge outcomes is the single most important goal in the management of acute heart failure syndromes.