Diuretics and vasodilators have been the cornerstone of heart failure (HF) therapy for decades. Although not shown to reduce mortality, diuretic and vasodilator therapy remain commonplace for treating acute decompensated HF, with diuretics being the mainstay of therapy for the removal of excess fluid in all patients with HF. This article discusses results of recent trials concerning diuretic or vasodilator therapy and HF, including the Diuretic Optimization Strategies Evaluation (DOSE) trial, the Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload to Assess Treatment Effect on Congestion and Renal Function (PROTECT), and the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST), as well as results from the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial and the Preliminary Study of Relaxin in Acute Heart Failure (Pre-RELAX-AHF).