IL-33 (interleukin 33) is type of cytokine designated an alarmin, which is released under stress conditions or by cell death to induce protective measures in neighboring cells.1 It signals via the ST2 (suppression of tumorigenicity 2) receptor, which is also expressed as a truncated and soluble form that acts as a decoy receptor soluble ST2 (sST2).2 Substantial evidence supports the use of sST2 measurement as an indicator of cardiac stress and remodeling in hypertension, heart failure, cardiomyopathies, and aortic stenosis (AS). However, as discussed here, there are gaps in our understanding of the IL-33/sST2 axis, including the source of the components, stimuli for their expression and release, what it actually assesses, and the role of immune cells. Moreover, as discussed, the fundamental assumption that Il-33 has beneficial actions that are thwarted by sST2 requires further scrutiny.