Acute appendicitis is the most common surgical emergency in children, with a lifetime risk estimated between 2% and 9%.¹ It can be classified as simple appendicitis (SA) or perforated appendicitis (PA), also referred to as complicated appendicitis; clinically, the latter is defined in the presence of macroscopic perforation and/or 4-quadrant pus and/or intra-abdominal mass/abscess or free fecalith.² Although the mortality risk for SA is reported as low as 0.1%, PA has a 5% mortality risk, highlighting the need for timely and accurate diagnosis and treatment.³ In this issue of JAMA Pediatrics, Dhillon et al⁴ aimed to identify blood-based biomarkers for use as clinical molecular diagnostics to differentiate between SA and PA in children.