The use of surface-enhanced Raman scattering (SERS) as a technique for detecting small amounts of (bio)chemical analytes has become increasingly popular in various fields. While gold and silver nanostructures have been extensively studied as SERS substrates, the availability of other types of substrates is currently expanding the applications of this spectroscopic method. Recently, researchers have begun exploring two-dimensional (2D) materials (e.g., graphene-like nanostructures) as substrates for SERS analysis. These materials offer unique optical properties, a well-defined structure, and the ability to modify their surface chemistry. As a contribution to advance this field, this concept article highlights the significance of understanding the chemical mechanism that underlies the experimental Raman spectra of chemisorbed molecules onto 2D materials’ surfaces. Therefore, the article discusses recent advancements in fabricating substrates using 2D layered materials and the synergic effects of using their metallic composites for SERS applications. Additionally, it provides a new perspective on using Raman imaging in developing 2D materials as analytical platforms for Raman spectroscopy, an exciting emerging research area with significant potential.