Glaucoma is one of the leading causes of visual impairment and blindness. Lowering intraocular pressure (IOP) is the only proven means to slow or halt disease progression among those at higher risk of developing glaucoma and those with early to moderate or more advanced glaucoma. Recent publications have highlighted the potential for increased rates or likelihood of worsening glaucoma among those with larger IOP swings within defined time periods. The purpose of this systematic, comprehensive review and analysis of the literature was to assess the state of knowledge in the area of IOP changes over time and the potential impact of such changes on treatment. Current literature indicates that a random IOP measurement is a poor surrogate for IOP levels throughout the day and across visits. We address several key questions: 1) What is the best way to measure IOP? 2) Should multiple IOP measurements be performed in a day in the office (short-term IOP fluctuation)? 3) Is measurement at night required? 4) Should clinicians begin to assess long-term IOP fluctuation in patients under stable treatment (across days or visits)? and 5) Should therapy choices be influenced by properties of different treatment options relative to short- or long-term IOP fluctuation?