Endocrine signaling networks control diverse biological processes and life history traits across metazoans. In both invertebrate and vertebrate taxa, steroid hormones regulate immune system function in response to intrinsic and environmental stimuli, such as microbial infection. The mechanisms of this endocrine-immune regulation are complex and constitute an ongoing research endeavor facilitated by genetically tractable animal models. The 20-hydroxyecdysone (20E) is the major steroid hormone in arthropods, primarily studied for its essential role in mediating developmental transitions and metamorphosis; 20E also modulates innate immunity in a variety of insect taxa. This review provides an overview of our current understanding of 20E-mediated innate immune responses. The prevalence of correlations between 20E-driven developmental transitions and innate immune activation are summarized across a range of holometabolous insects. Subsequent discussion focuses on studies conducted using the extensive genetic resources available inDrosophilathat have begun to reveal the mechanisms underlying 20E regulation of immunity in the contexts of both development and bacterial infection. Lastly, I propose directions for future research into 20E regulation of immunity that will advance our knowledge of how interactive endocrine networks coordinate animals’ physiological responses to environmental microbes.