Preventive chemotherapy (PCT) programmes are used to control five of the highest burden neglected tropical diseases (NTDs): soil-transmitted helminth infections (hookworm, ascariasis, and trichuriasis), lymphatic filariasis, schistosomiasis, onchocerciasis, and trachoma. Over the past decade, new resource commitments for the NTDs have enabled such programmes to intensify their control efforts, and for some diseases, to shift from goals of morbidity control to the interruption of transmission and elimination. To successfully eliminate the parasite reservoir, these programmes will undoubtedly require prolonged, high treatment coverage. However, it is important to consider that even when coverage levels reach an acceptable proportion of the target population, there may be a considerable gap between coverage (those who receive the drug) and compliance (those who actually consume the drug)—a topic of fundamental and perhaps underestimated importance. We conducted a systematic review of published literature that investigated compliance to PCT programmes for NTD control and elimination. Databases searched included PubMed/Medline, Web of Knowledge (including Web of Science), OVID, and Scopus. Data were collected on compliance rates, reasons for non-compliance, as well as the heterogeneity of compliance definitions and calculations across programmes and studies. A total of 112 studies were selected for inclusion. The findings of the review revealed substantial heterogeneity across compliance terms and definitions; an imbalance of available studies for particular disease areas and countries; and finally, a lack of longitudinal compliance studies to properly investigate the role of systematic non-compliance. The lack of consistency among reporting of compliance data can result in under- or over-estimating compliance in a population, and therefore has serious implications for setting and reaching elimination targets. Reframing of the guidelines on compliance definitions coupled with an urgent call for longitudinal research in systematic non-compliance should be essential elements in the programmatic shift from control to elimination.