Chronic pulmonary complications, including pulmonary hypertension (PH), are common in sickle cell disease (SCD), especially in adults with sickle cell anemia (SCA). The underlying pathophysiology is complex and variable, involving multiple biological systems. Recent emphasis has been placed on the pleotropic biological factor nitric oxide (NO). An elevated tricuspid regurgitant velocity (TRV) appears to have limitations in specificity in SCA, but may indicate the presence of PH, a diagnosis confirmed by right heart catheterization. TRV has been used in recent clinical trials to identify or define subjects with PH for enrollment into PH-specific interventions; these include sildenafil, which enhances NO-induced vasorelaxation. Results from a controlled trial show no benefit and an unexpected increase in adverse events, emphasizing the biological complexities of SCA. Management remains principally supportive, includes recognition and treatment of comorbidities, and may incorporate individualized PH-specific strategies (despite recent trials) based on appropriate diagnostic testing. Ultimately, therapy is likely to be multimodal and tailored to the processes identified to be the most contributory in a given individual. Based on the relative prevalence of the conditions, routine screening for asthma in children with SCD and by Doppler echocardiography to measure TRV as an initial screen for PH in adults with SCA may be warranted. Data are limited regarding the clinical utility of screening in other forms of SCD and the pediatric population. This article offers an individual perspective on practical and challenging clinical considerations.