In this issue of JAMA Surgery, Hieken et al present the first blinded, prospective trial analyzing gene expression profiling (GEP) in patients with melanoma undergoing sentinel lymph node biopsy (SLNB). The authors introduce the Merlin assay and hypothesize it can identify who can safely forgo SLNB, with a long-term objective of determining the test’s prognostic significance for patients with node-negative disease. Results focus on the former objective. The assay combines GEP with patient age and tumor depth (clinicopathological factors plus GEP, or CP-GEP) to classify a “low” or “high” risk of SLNB metastases in 1761 patients. This study had strict eligibility criteria, resulting in overall SLNB positivity of 17% and low-risk-score SLNB positivity of 7.1%. While it came very close, the low risk score did not reach the National Comprehensive Cancer Network arbitrary benchmark, which indicates SLNB can be excluded if the risk of SLN metastasis is less than 5%.