Recently, the dramatic emergence of antimicrobial resistance has received attention from World Health Organization. Synthetic antimicrobial peptides (SAMPs) are considered new weapons to fight against infections caused by multi-drug resistant pathogens. Here, the authors provide an overview of the current research on SAMPs. The focus is SAMPs, how to design them, which features must be considered during design, and comparison with natural peptides. This review also includes a discussion about the natural AMPs, mechanisms of action and applications as new drugs or even as adjuvants molecules to enhance commercial drugs activity. The advances in chemical synthesis have reduced the cost to produce synthetic peptides open ways to achieve new antimicrobial agents. Therefore, synthetic peptides are new promising molecules to safeguard human and animal health.