Suppression of tumorigenicity 2 (ST2, also known as interleukin [IL]-1 receptor–like-1) is an IL-1 receptor family member with transmembrane (ST2L) and soluble isoforms (sST2). ST2L is a membrane-bound receptor, and IL-33 is the functional ligand for ST2L. sST2, a soluble truncated form of ST2L, is secreted into the circulation and functions as a “decoy” receptor for IL-33, inhibiting IL-33/ST2L signaling. Blood concentrations of sST2 are increased in inflammatory diseases and heart disease and are considered a valuable prognostic marker in both conditions. In multiple clinical trials, sST2 has emerged as a clinically useful prognostic biomarker in patients with cardiac diseases. Interestingly, sST2 even provides prognostic information in low-risk community-based populations. In this review, we will discuss analytical considerations of measuring circulating sST2 including pre-analytical issues, such as in vitro stability of sST2, biological variation of sST2, and postanalytical issues, such as reference ranges and comparisons to diseased cohorts.