Heart failure (HF) is a complex syndrome that requires tailored and patient-centered treatment. Sodium-glucose cotransporter 2 inhibitors (SGLT2is) constitute one of the four pillars of the medical treatment of HF. However, the 2023 ESC guidelines treat HF as a single entity without making clear distinctions in phenotypes according to etiology. This creates a “gap in knowledge”, causing much debate about the applicability of these drugs in peculiar clinical settings that are etiological and/or predisposing clinical conditions for HF. Furthermore, considering the variety of etiologies and different pathophysiological backgrounds of HF, one might question whether the use of SGLT2is is equally beneficial in all types of HF and whether certain drug-related properties may be exploited in different contexts. For example, SGLT2is can improve the metabolic and inflammatory state, which is fundamental in ischemic heart disease. Anti-inflammatory power can also play a paramount role in myocarditis or cardiotoxicity, while improving the congestive state and reducing filling pressure may be even more fundamental in restrictive heart disease or advanced heart disease. This review aims to gather the evidence currently present in the literature concerning the advantages or the disadvantages of using these drugs in these particular clinical settings, with the goal being an optimized and highly personalized treatment for HF.