The innate immune system is an organism's first line of defense against an onslaught of internal and external threats. The downstream adaptive immune system has been a popular target for therapeutic intervention, while there is a relative paucity of therapeutics targeting the innate immune system. However, the innate immune system plays a critical role in many human diseases, such as microbial infection, cancer, and autoimmunity, highlighting the need for ongoing therapeutic research. In this review, we discuss the major innate immune pathways and detail the molecular strategies underpinning successful therapeutics targeting each pathway as well as previous and ongoing efforts. We will also discuss any recent discoveries that could inform the development of novel therapeutic strategies. As our understanding of the innate immune system continues to develop, we envision that therapies harnessing the power of the innate immune system will become the mainstay of treatment for a wide variety of human diseases.