Renal dysfunction is highly prevalent in patients with heart failure. Furthermore, worsening renal function in patients with acute decompensated heart failure (ADHF), the so-called cardiorenal syndrome, impacts short and long-term morbidity and mortality. In recent years, more evidence has surfaced from clinical trials and heart failure registries that a complex cross-talk between the kidney and heart in patients with ADHF exists. Meanwhile, management of patients presenting with ADHF and concomitant renal dysfunction continues to be challenging. Therefore, understanding the interaction of the heart and kidneys is pivotal in tailoring therapy of these patients. We have extensively reviewed the pathophysiology of ADHF, the role of neurohoromones as well as other biomarkers and predictors of mortality in these patients based on the current evidence. Moreover, we have discussed the current and future pharmacologic and non-pharmacologic therapies for treatment of this deadly disease. The strength of the evidence is limited, however, due to a paucity of randomized controlled trials in this patient population. What is evident from current national statistics; however, are the poor results in treating the congestion of ADHF. In this regard, the role of secondary hyperaldosteronism is discussed in the diuretic section as well as diuretic resistance in ADHF. In conclusion, since renal function is the single most important prognostic factor in the outcome of patients with ADHF, a better understanding of the pathophysiology of the cardiorenal syndrome is needed to target therapy and ultimately improve the mortality of patients with ADHF.