A significant proportion of patients with spondyloarthritis (SpA) have peripheral enthesitis. Data suggest that psoriatic arthritis (PsA) patients with enthesitis have a higher disease burden than those without enthesitis. Over the past decade, there has been a proliferation of treatment options for spondyloarthropathy. These medications target multiple signaling pathways, including tumor necrosis factor (TNF), interleukin (IL)-17A, IL-12/23, IL-23, thymus (T)-cell co-stimulation, intracellular Janus kinases, and phosphodiesterase enzymes. As a key domain in SpA, enthesitis outcomes are included in pivotal trials of these agents and are reported as secondary outcome measures. One significant limitation is that the clinical evaluation of enthesitis relies on eliciting tenderness on palpation and is insensitive when compared with imaging. Furthermore, direct comparisons between studies are not available due to the use of different outcome measures, lack of consistent and comprehensive reporting outcomes, and subgroup analyses with a lower number of patients with enthesitis. This systematic review describes the epidemiology, pathophysiology, and available targeted therapies against enthesitis, as well as a detailed report of their efficacy. One major trend identified during this review is incomplete reporting of outcome measures, as many studies reported proportions of enthesitis prevalence. Factors that affected responsiveness in clinical trials included the entheseal instrument used, the number of subjects available for comparison, as well as the therapeutic agent. In general, anti-TNF and anti-IL-17 agents, as well as Janus kinase inhibitors, show moderate responsiveness for enthesitis. The data for IL-23 targeting is contradictory.