Jet lag syndrome (JLS) is a clinical syndrome of disrupted nocturnal sleep and daytime neurocognitive impairment which occurs in the context of rapid transmeridian travel. Many strategies for treatment of JLS exist, and include hypnotics to enhance nocturnal sleep, chronotherapeutic approaches (eg, light therapy, melatonin, or gradual schedule shifting), and alerting agents to counter daytime sleepiness. Safety concerns have prompted renewed interest in managing JLS-associated excessive daytime sleepiness (JLSAEDS). Off-label use of the newer alerting agents modafinil and armodafinil is increasing for this indication, often at the specific request of patients. In order to better evaluate the potential risks and benefits of these medications for the management of JLSAEDS, clinicians must be aware of what is known – and still not known. In this article, the pharmacology and pharmacokinetics of modafinil and armodafinil are reviewed, along with evidence for their efficacy in treating sleepiness associated with narcolepsy, obstructive sleep apnea and shift work sleep disorder. Clinical trial data for use of alerting agents in the management of JLSAEDS are limited to one three-day trial involving armodafinil, dosed in the morning to treat JLSAEDS in the setting of eastbound transmeridian travel. This study showed improvement in objective measures of daytime sleepiness at doses of 50 and 150 mg per day. However, global impression of clinical severity of symptom scores only improved on day 1 for those patients receiving 150 mg, and were otherwise not superior to placebo. Consideration for the use of modafinil or armodafinil for the treatment of sleepiness associated with JLS involves careful integration of patient-reported goals, a review of medical contraindications, and an awareness of rare adverse events. More research is needed in order to identify those who are most likely to benefit from this intervention and better define the risk-benefit ratio for this indication.