During the last 10 years, the number of alternative Haematopoietic stem cell transplantations (HSCTs) performed on children in Europe has increased significantly and has reached 61% of the allografts. In this paper, we provide practical guidelines to help define an algorithm for the treatment of children relapsing during or after first-line chemotherapy for ALL and lacking a matched sibling donor. A simultaneous search for an unrelated donor and for a cord blood unit should be started. This study focuses mainly on the effects of some factors on survival in an effort to highlight the influence that these factors have on our choices. Matching the patient for HLA-A, -B, -C and -DRB1 alleles remains the top priority: a single HLA class I or II allele mismatch has no influence on survival, while multiple mismatching for more than one class I allele and simultaneous disparities in class I and II alleles increase mortality. The impact of additional mismatches for HLA-DQ and -DP loci on survival is still controversial. Young donor age is the most important factor that has a significant effect on better survival from among several other factors, including CMV sero-status, gender and ABO. An 18- to 30-year-old, 8/8 allele-matched donor (excluding allele matching at DQB1) or for many teams 10/10 allele-matched donor; or a 4 out of 6 (considering Ag HLA-A, -B and allelic typing of DRB1) CB unit containing more than 3.0 x 10(7) nuclear cells is considered by most institutions. The choice should be made on the basis of urgency. If a donor or a CB unit is not found within an appropriate time frame, generally less than 3 months after obtention of remission, haploidentical HSCT should be offered. Some institutions consider haploidentical HSCT the second therapeutic option when a matched donor is not available.