It is well known that over the time each species has directed a specific function of its metabolic activity for survival, development and perpetuation, towards a sustained seeking for a balance with the surrounding environment. In this respect, plants became a major point of interest for the pharmaceutical industry due to their capacity of synthetizing organic compounds with specific pharmacological activity, most of them as secondary metabolites. Several major classes of chemical compounds, i.e. flavones, phenolics, terpenoids and essential oils, alkaloids, lectins and polypeptides, and polyacetylenes are phytochemicals with important antimicrobial activity and, besides them, some other natural compounds involved in inter-kingdom communication, such as quorum sensing molecules or natural antimicrobial peptides. These compounds have been proposed as potential alternatives to antibiotics for fighting infectious diseases. Extensive research has been made regarding the antimicrobial efficiency for a plethora of such natural compounds, but, unfortunately, lesser importance has been given to the occurrence of microbial resistance to them. In this respect, our aim was to review the literature, highlighting the latest findings on this topic, for a comprehensive view regarding the risk of using antimicrobials from natural sources in selecting microbial resistance. Keywords: Microbial resistance, natural compounds, antibiotics.