• Documented informed consent of the participant and/or legally authorized representative

‣ Assent, when appropriate, will be obtained per institutional guidelines

• Registered into Risk Evaluation and Mitigation Strategies (REMS) program

• Age: 12-40 years

• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2

• Have a diagnosis of sickle cell disease, be at a high risk for disease related morbidity or mortality, which must be defined by one of the following disease status criteria:

‣ Significant neurologic event (stroke) or any neurological deficit lasting \> 24 hours; or increased transcranial Doppler velocity (\> 200 m/s).

⁃ History of one or more episodes of acute chest syndrome (ACS) in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. asthma therapy and/or hydroxyurea).

⁃ History of one or more severe vaso-occlusive pain crises per year in the 2-year period preceding enrollment despite the institution of supportive care measures (i.e. a pain management plan and/or treatment with hydroxyurea).

⁃ Recurrent priapism requiring medical therapy.

⁃ Osteonecrosis of two or more joints despite the institution of supportive care measures.

⁃ Prior treatment with regular red blood cell (RBC) transfusion therapy, defined as receiving 8 or more transfusions per year for \> 1 year to prevent vaso-occlusive clinical complications (i.e. pain, stroke, and acute chest syndrome)

⁃ Echocardiograph finding of tricuspid valve regurgitation jet (TRJ) velocity \>= 2.5 m/sec.

• Have a related donor who is matched on at least 8/10 human leukocyte antigen (HLA)-A, B, C, and DRB1 Loci

• Total bilirubin =\< 2.5 x upper limit normal (ULN( (unless has Gilbert's disease) (performed within 30 days prior to day 1 of protocol)

• Aspartate aminotransferase (AST) =\< 1.5 x ULN (performed within 30 days prior to day 1 of protocol)

• Alanine aminotransferase (ALT) =\< 1.5 x ULN (performed within 30 days prior to day 1 of protocol)

• Creatinine clearance (CrCl) of \>= 60 mL/min per 24 hour urine test or the Cockcroft-Gault formula (performed within 30 days prior to day 1 of protocol)

• If not receiving anticoagulants: International Normalized Ratio (INR) OR Prothrombin (PT) =\< 1.5 x ULN (performed within 30 days prior to day 1 of protocol)

‣ If on anticoagulant therapy: PT must be within therapeutic range of intended use of anticoagulants

• If not receiving anticoagulants: Activated Partial Thromboplastin Time (aPTT) =\<1.5 x ULN (performed within 30 days prior to day 1 of protocol)

‣ If on anticoagulant therapy: aPTT must be within therapeutic range of intended use of anticoagulants

• Left ventricular ejection fraction (LVEF) \>= 50% (performed within 30 days prior to day 1 of protocol)

‣ Note: To be performed within 28 days prior to Day 1 of protocol therapy.

• If able to perform pulmonary function tests: Forced expiratory volume in 1 second (FEV1), force vital capacity (FVC), and diffused lung capacity of carbon monoxide (DLCO) (diffusion capacity) \>= 50% of predicted (corrected for hemoglobin)

‣ If unable to perform pulmonary function tests: Oxygen (O 2) saturation \> 92% on room air

⁃ Note: To be performed within 28 days prior to Day 1 of protocol therapy.

• Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma regain \[RPR\])

‣ If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed

• Meets other institutional and federal requirements for infectious disease titer requirements

‣ Note Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

‣ If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be require.

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least Six months after the last dose of protocol therapy.

‣ Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)

• DONOR: Age =\< 60 years

• DONOR: Medical history and physical examination confirm good health status as defined by institutional standards

• DONOR: Serologies for: Hepatitis B (HBV) Core Antibody, HIV I/II Antibody, human T-lymphotropic virus (HTLV) - I/II antibody, HCV antibody, Hepatitis B surface antigen, Serologic Test for Syphilis, HIV-1/HCV/HBV nucleic acid, West Nile virus nucleic acid, Trypanosoma cruzi antibody, Cytomegalovirus (CMV) antibody, (AKA: Donor Room Serologies)

• DONOR: Female donors of childbearing potential must have a negative serum or urine beta human chorionic gonadotropin (b-HCG) test within 30 days of initiation of conditioning, 30 days of patients admission for conditioning and 7 days of mobilization or bone marrow harvest.

• DONOR: The donor must be informed of the investigational nature of this study and have signed a consent form in accordance with Federal Guidelines and the guidelines of the participating institution