In heart failure with reduced ejection fraction, edema and congestion are related to reduced cardiac function. Edema and congestion are further aggravated by chronic kidney failure and pulmonary abnormalities. Furthermore, together with edema/congestion, sodium/water retention is an important sign of the progression of heart failure. Edema/congestion often anticipates clinical symptoms, such as dyspnea and hospitalization; it is associated with a reduced quality of life and a major risk of mortality. It is very important for clinicians to predict the signs of congestion with biomarkers and, mainly, to understand the pathophysiological findings that underlie edema. Not all congestions are secondary to heart failure, as in nephrotic syndrome. This review summarizes the principal evidence on the possible roles of the old and new congestion biomarkers in HFrEF patients (diagnostic, prognostic, and therapeutic roles). Furthermore, we provide a description of conditions other than congestion with increased congestion biomarkers, in order to aid in reaching a differential diagnosis. To conclude, the review focuses on how congestion biomarkers may be affected by new HF drugs (gliflozins, vericiguat, etc.) approved for HFrEF.