Regional nodal status remains one of the most important prognostic factors in several solid tumors including melanoma, breast cancer, and gastrointestinal malignancies. However, despite the accuracy of lymph node (LN) staging, patients who are LN negative are still at risk for development of recurrence and distant metastasis. As such, numerous molecular studies have focused on genetic and transcriptome changes in primary and metastatic tumors to discover molecular determinants that can predict aggressive metastatic disease and/or correlated to clinical outcomes. More recently, epigenetic aberrations have been investigated in solid cancers and are associated with tumorigenesis and disease progression. These epigenetic alterations have demonstrated potential utility as diagnostic and prognostic biomarkers and are being developed into novel targeted treatment strategies, as epigenetic changes can be reversed by appropriate drugs. If patients who are at increased risk of developing metastases or recurrence can be accurately identified, this will help stratify patients into more appropriate treatment and follow-up. This review discusses some of the recent studies on regional LN metastases in melanoma, breast cancer, and colorectal cancer, focusing on the potential clinicopathological utility of epigenetic aberrations in the management of cancer patients.