Worsening heart failure (HF) is associated with a high risk of death and HF hospitalization. A systematic search was conducted on PubMed (MEDLINE), using the MeSH terms Heart failure + Worsening + Treatment + Vulnerable period up to February 2023. Original data from clinical trials, and observational studies were critically analyzed. Although the vulnerable period has been traditionally limited to the first 6 months after HF hospitalization, the fact is that there are other clinical scenarios in which the patient is particularly vulnerable. These vulnerable patients may also include those that require parenteral administration of diuretics in the day hospital or emergency department, those in which the increase of oral diuretic dose in an outpatient setting is needed to relief congestive symptoms, as well as those that remain symptomatic despite treatment. On the other hand, HF is a complex disease in which different neurohormonal systems are involved. Therefore, to actually reduce the HF burden, a comprehensive management, targeting all the neurohormonal systems that are involved in the pathogenesis of HF, through the use of those drugs that have demonstrated to positively modify the clinical course of HF, is needed.