This section explores the strategies and methodologies employed in the design and discovery of novel AMPs, transitioning from natural templates to therapeutic candidates. The process can be broadly divided into two phases. The first phase, hit generation, focuses on leveraging existing structures and learning from natural and synthetic AMPs to generate novel candidates with potential antimicrobial activity. The second phase, hit-to-lead optimization, delves into refining these candidates to enhance selectivity and activity while minimizing toxicity. Structural models and advanced computational approaches play a pivotal role in navigating the delicate balance between efficacy and safety, providing a foundation for rational AMP design and development.