This chapter discusses the change in the paradigm of drug discovery, shifting from the “magic bullet” concept to the “magic shotgun” or “silver bullet” approach, i.e., one-compound—multiple-target model. The concept of polypharmacology and its aspects related to drug discovery and development, such as drug attrition and drug repurposing are presented. Computational multi-target drug design strategies are discussed, particularly focusing on docking approaches (forward and inverse) and by presenting relevant examples available in the literature.