Abstract: Uncontrolled and chronic inflammatory states in the central nervous system (CNS) are the hallmark of neurodegenerative pathology and every injury or stroke-related insult. The key mediators of these neuroinflammatory states are glial cells known as microglia, the resident immune cell at the core of the inflammatory event, and astroglia, which encapsulate inflammatory insults in proteoglycan- rich scar tissue. This gliotic scar blocks significant portions of healthy axonal networking, preventing regeneration. Since most neuroinflammation is exclusively based on the responses of said microglia, their phenotypes are suggested to follow those of macrophages; M1 and M2 are opposites of pro- and anti-inflammation. However, microglial phenotypes have been identified to be on an inflammatory spectrum encompassing developmental, homeostatic, and reparative behaviors as opposed to their ability to affect devastating cell death cascades and scar tissue formation. More recent work has suggested that microglia also undergo a priming phenotype as a response to unresolved or sustained chronic inflammation, which is thought to be associated with neurodegenerative and neuropsychiatric disorders. Several research groups have recently focused on peptide discovery to target these phenotypes, find their novel mechanisms, and mediate or re-engineer their actions. Peptides retain the diverse function of proteins but significantly reduce the activity dependence on delicate 3D structures. A handful of peptides targeting unique microglia phenotypes have emerged from discovery experiments. With the hope of mediating deleterious cell-killing behaviors or promoting beneficial outcomes in neuroinflammation, a great need for said peptide discovery exists. This article highlights the benefits, challenges, and potential resolutions in discovering peptide and peptide tools for microglia physiology and pathophysiology. A summary of studies is shown in Table 1 and an example is shown in Figure 1.