Surface-enhanced Raman spectroscopy (SERS) is a vibrational spectroscopic technique with molecular fingerprinting capability and high sensitivity, even down to the single-molecule level. As it is 50 years since the observation of the phenomenon, it has now become an important task to discuss the challenges in this field and determine the areas of development. Electromagnetic enhancement has a mature theoretical explanation, while a chemical mechanism which involves more complex interactions has been difficult to elucidate until recently. This article focuses on the 2D material-based platforms where chemical enhancement (CE) is a significant contributor to SERS. In the context of a diverse range (transition metal dichalcogenides, MXenes, etc.) and categories (insulating, semiconducting, semimetallic, and metallic) of 2D materials, the review aims to realize the influence of various factors on SERS response such as substrates (layer thickness, structural phase, etc.), analytes (energy levels, molecular orientation, etc.), excitation wavelengths, molecular resonances, charge-transfer transitions, dipole interactions, etc. Some examples of special treatments or approaches have been outlined for overcoming well-known limitations of SERS and include how CE benefits from the defect-induced physicochemical changes to 2D materials mostly via the charge-transport ability or surface interaction efficiency. The review may help readers understand different phenomena involved in CE and broaden the substrate-designing approaches based on a diverse set of 2D materials.