Thyroid nodules are among the most common thyroid diseases, with higher female gender prevalence. The crucial clinician’s diagnostic dilemma is to distinguish benign and malignant thyroid nodules. Benign nodules are far more common than malignant, while papillary thyroid carcinoma predominates among malignant nodules. There is no unique and completely accurate diagnostic test, method, or even biomarker that would indicate with great certainty the malignant nature of thyroid nodules. Most thyroid tumors developed due to changes in genes, where protein products regulate mitogen activated protein kinase/ extracellular signal-regulated kinases and protein kinase B/ phosphoinositide 3-kinase signaling pathways that stimulate proliferation and inhibit apoptosis of cells. Today, we know a certain number of point mutations and chromosome rearrangements present in malignant tumors, but their diagnostic usage is not significant yet. Phospholipids, free fatty acids, and nitric oxide are essential for the thyroid gland function. Thus, deranged levels of such parameters in serum and thyroid aspiration biopsy washout could have a prognostic impact on malignant thyroid diagnostics.