Intracerebral hemorrhage (ICH) stands out among strokes, both for the severely morbid outcomes it routinely produces, and for the striking deficiency of defenses possessed against the same. The brain damage caused by ICH proceeds through multiple pathophysiological mechanisms, broadly differentiated into those considered primary, arising from the hematoma itself, and the secondary consequences of hematoma presence and expansion thereof. A number of interventions against ICH and its sequelae have been investigated (e.g., hemostatic therapies, blood pressure control, hematoma evacuation, and a variety of neuroprotective strategies), but conclusive demonstrations of clinical benefit have remained largely elusive. In this review, we begin with a description of these interventions and the trials in which they have been implemented, coupled with an attempt to account for their failure. Possible causes discussed include iatrogenic injury during hematoma evacuation, secondary injury initiated by hematoma persistence after evacuation, and inadequate therapeutic power arising from an excessively narrow focus on a single component of the complex pathophysiology of ICH injury. To conclude, we propose several strategies, such as enhancing endogenous hematoma resolution, hematoma evacuation-based neuroprotection, and multi-targeted therapy, that hold promise as prospects for the extension of anti-ICH therapy into the domain of clinical significance. © 2020 Elsevier B.V.