The increasingly widespread availability of next-generation sequencing has led to its incorporation as a diagnostic tool in pathology and a modality for identifying targetable alterations. However, sequencing is still a somewhat expensive and time-consuming. Here, we discuss tumor types for which (1) molecular testing is not generally indicated, (2) surrogate immunohistochemical markers have rendered molecular testing unnecessary, or (3) sequencing is important for diagnostic and therapeutic purposes. We also provide a practical framework to assist in decision-making for molecular testing of both classified and unclassified mesenchymal neoplasms, reflecting our practice in a tertiary sarcoma referral center.