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More cancer therapies are being administered via an oral route. This paradigm shift in providing cancer treatment has been met with both excitement and significant challenges for oncology practitioners. Multiple factors can impact the ability for patients to initiate and stay on oral cancer therapy. A major factor in patient adherence with oral cancer therapies is management of side effects. Side effects from therapy not only have a negative impact on a patient's quality of life but also can cause serious complications. In addition, they can impact the patient's ability to stay on therapy at optimal doses. New strategies must be designed for educating patients and caregivers, as well as for patient management and follow-up. When side effects are not managed appropriately, patients are less likely to want or be able to adhere to established treatment plans. This article explores several challenges related to the use of oral cancer therapies, with a focus on side effects seen with various classes of new targeted agents. Evidence-based practice strategies and areas in need of additional exploration and research are reviewed.