Cardiovascular diseases (CVDs), involving various disorders of blood vessels and the heart, remain the leading cause of premature mortality and rising healthcare costs in the world. According to the Global Burden of Disease study, which estimated the health status of the population for the period from 1990 to 2019, cases of cardiovascular disease have almost doubled, while an age dependency of mortality with a rapid onset from the age of 60 was observed [1]. Apart from age, other risk factors for cardiovascular events and heart failure (HF) are high blood pressure, obesity, high cholesterol, coronary heart disease, diabetes, smoking and genetics [2]. In general, the term HF describes a heart that is no longer pumping properly due to weakness or stiffness, resulting in symptoms such as reduced energy, difficulties in walking and performing daily activities, swelling of the legs and abdomen [3]. Basically, HF can be classified according to the side of the heart affected (left-sided or right-sided HF), the pumping capacity (HF with reduced (<50%) or preserved (>50%) ejection fraction (EF)) or the course of the disease (acute or chronic) [[4], [5], [6]]. Obviously, HF is a complex syndrome associated with reduced cardiac function, significant morbidity and mortality and a generally poor quality of life. Pathological hallmarks of HF are cardiac remodeling and cardiomyocyte cell death, which is accelerated by molecular factors such as inflammatory or oxidative stress and impaired proteostasis [[7], [8], [9]]. As cardiomyocytes are post-mitotic cells with limited regenerative capacity, adequate protein turnover is particularly important to prevent the accumulation of unfolded and damaged proteins. Defined turnover of damaged, misfolded, modified or no longer required proteins is ensured by various extra- and intracellular proteases, including the proteasome [10]. With regard to proteasome failure, a compensatory effect of autophagy has been described [11]. The use of proteasome inhibitors such as MG132 increased the autophagic degradation of proteasome substrates [12]. Analyzing the interplay of both pathways can help to understand the general changes in proteolysis and their contribution to the development of HF. Therefore, this review will provide a brief introduction into the role of the proteasome in different phenotypes of HF presenting recent studies focusing on the immunoproteasome (i20S) in HF. In addition, a selection of i20S inhibitors and their mode of action will be introduced. Finally, the interplay between the i20S and autophagy in HF will be highlighted in terms of potential signaling pathways to outline possible strategies for preventing cardiotoxicity and HF.