When clinical trial enrollment is not an option for seriously ill patients whose illnesses have not responded to approved treatment options, those patients and their physicians may consider gaining access to investigational therapies through a pathway established by the Food and Drug Administration (FDA) called expanded access. However, recent events have highlighted the challenging dynamics involved in accessing investigational therapies through expanded access that include a complex interplay of factors involving the patient, physician, drug company, FDA, and, increasingly, social media. The authors offer several potential strategies to streamline what is otherwise an arduous process for all involved. (1) The drug company should prospectively determine whether it will establish an expanded access program for specific drugs. (2) A central clearinghouse for companies should support registration of expanded access drugs for suitable patients. (3) The determination of whether a patient fits criteria would be made by an independent review board of clinicians. (4) An independent coordinating center is needed; academic health centers are ideally suited for that role. (5) Adequate financing of the costs of therapy need to be in place to make expanded access a reality, given frequent lack of payer coverage for therapies. (6) Further enhancement of regulatory pathways, approaches, or rules would promote expanded access. (7) Patients should explicitly acknowledge the limited data available. (8) There should be a shared, secure, technical platform to facilitate expanded access. All the authors' strategies present important prospects for improving treatment options for the most seriously ill patients.