Trained immunity is, in its name and definition, a paradox. It is both new and old. While trained immunity was written as a definition into the scientific literature as recently as 2011, this process is one of nature’s oldest tricks. Even plants have the capacity to alter their gene expression with epigenetic modulations to better respond to a future threat; we refer to this today as training. It is both activation and suppression. Early studies in trained immunity focused on Bacille Calmette-Guérin (BCG) and β-glucan as potent activators of pro-inflammatory trained immunity. However, we now know that epigenetic and metabolic reprogramming goes in both directions. It can increase or suppress inflammation (of various types) depending on the initial training stimuli. It is both innate memory and not immunologic memory. We will always understand that antigen-specific immunologic memory of the adaptive immune system is one of evolution’s most elegant systems. Yet, we know now that innate cells, and other cells beyond the immune system including stromal cells, can remember their past through the epigenetic code we call training. It is mechanistic biology and engineering. While the mechanisms underlying trained immunity must be answered through fundamental biochemical methods, the interdisciplinary nature calls for engineering approaches to answer these questions quickly. We start the conversation on this topic in Chapter 1. I began my PhD with one core question: Is inflammation required to induce trained immunity? The answer, again, became its own paradox. Yes and no. In Chapter 2, we learn that trained immunity can be induced with non-immunogenic small molecules which were not associated with autoinflammatory conditions nor with pathogens. In Chapter 3, we learn that steroids, traditionally immunosuppressive compounds, induce training that results in amplifications in the pro-inflammatory response, alongside dozens of other novel inducers of training. We also learn that these training programs are stimulus specific. They are unique. Trained immunity induced by inflammation is distinctly different from trained immunity induced in the absence of inflammation. Because they are different, applying non-inflammatory small molecule trained immunity to applications where β-glucan succeeded were not always a triumph. I discuss this in Chapters 4 and 5, testing these compounds in cancer, vaccination, and viral models. Together, this work is an expansion on what trained immunity is, what it can be, and, in some cases, what it fails to be.