Microbial products continue to represent one of the most interesting sources for the discovery and development of novel drugs. As a result of the massive screening of microbes since 1950, one of the most important hindrances encountered so far in screening microbial natural products is re-isolation of already discovered bioactive molecules. Thus, identifying known or undesirable compounds from natural product extracts at an early stage, indicated here as chemical dereplication, is a key step in the process, saving resources and speeding up the discovery process of novel drugs. In this mini-review, we highlight the analytical techniques commonly used to evaluate the novelty of microbial metabolites during screening and the advances that have been made in related technologies.