Sickle cell disease (SCD) is an autosomal-recessive genetic disorder that affects more than 3 million people worldwide. Sickle cell anemia, the most common form of SCD, is caused by a homozygous mutation in the β-globin gene that leads to erythrocyte sickling, vaso-occlusion, and hemolysis. Acute chest syndrome (ACS) is a type of acute lung injury and one of the leading causes of mortality in SCD. Current treatments for ACS are primarily supportive, and there is a critical need for rescue therapies. ACS is often a sequela of acute systemic vaso-occlusive crisis and preceded by thrombocytopenia. Although vaso-occlusion is known to occur in the lung, the pathophysiological mechanisms that incite lung injury have remained largely unknown. Using intravital microscopy of the lung in transgenic humanized SCD mice and live-cell imaging of SCD patient blood flowing in microfluidic platforms in vitro, Sundd and colleagues have discovered that vaso-occlusive crisis triggers occlusion of lung arterioles by P-selectin-dependent platelet-neutrophil embolic aggregates. Sundd and colleagues’ newer findings reveal that the platelet-neutrophil aggregation in SCD is secondary to platelet-inflammasome activation and interleukin-1β (IL-1β) dependent signaling in platelets and neutrophils. These findings also suggest that therapeutic inhibition of inflammasome or IL-1β innate immune pathway can be a potential therapy for ACS in SCD patients.