Infantile spasm (IS) is a distinct epilepsy syndrome characterized by epileptic spasms (the clinical seizure type) and hypsarrhythmia (the electrographic abnormality). IS is frequently accompanied by impaired neurodevelopment and is often associated with structural, genetic, or metabolic etiologies. Prompt treatment of this severe epileptic encephalopathy improves long-term outcomes but remains elusive in many situations. Despite common misconceptions, even patients with identified etiologies or preexisting developmental delay benefit from proven standard therapies, including adrenocorticotropic hormone (ACTH), oral corticosteroids, or vigabatrin. Treatment efficacy should be assessed with electroencephalography at 2 weeks, and an alternative therapy is indicated if epileptic spasms or hypsarrhythmia have not resolved. Collaboration with primary care providers is critical to mitigate the potentially serious adverse effects of standard treatments and also to provide developmental interventions. Although new approaches are on the horizon, addressing current challenges and opportunities now can dramatically improve patient outcomes.