Thyroid nodules are a common condition frequently encountered by practicing endocrinologists. A previous “one-size-fits-all” approach for when to obtain fine-needle aspiration (FNA) biopsy or refer for surgery has been replaced by a more nuanced assessment of available data to create individualized care decisions. Specifically, optimal thyroid nodule assessment demands an understanding of how ultrasound features, FNA cytology diagnosis, and increasing, molecular findings, inform thyroid cancer risks. These discrete results combine with patient factors, such as cancer risk or comorbidities, and patient preference and quality of life considerations, completing a holistic picture to address the fundamental decision: Whether to perform surgical resection for a thyroid nodule, or whether to observe. In recent times, describing ultrasound features has dramatically improved thyroid cancer risk assessment, but has also spawned numerous systems and criteria around the world for doing so, such as Thyroid Imaging Reporting and Data Systems (TI-RADS) from America, Korea, Europe, and others, as well as from the American Thyroid Association. The Bethesda System for Reporting Thyroid Cytopathology is an international standard that provides consistent categories and risk stratification, but undergoes periodic updates to terminology and estimated malignancy risks. Finally, new discovering in the molecular underpinnings of thyroid cancer have led to complex molecular testing platforms, but their use is limited by uncertainties regarding their ideal application and cost-effectiveness, especially globally. Nevertheless, molecular features are undoubtedly a future tool of thyroid nodule evaluation. These aspects represent a changing landscape for thyroid nodule management and can produce uncertainly in providers and patients. This lecture will bring an evidence-based focus to how to employ multimodality thyroid nodule assessment in the clinic and come to well-considered patient care decisions.