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Despite many advances in the management of cancer, a substantial portion of cancer patients will still suffer a relapse. Drug-resistance remains a major problem in dealing with malignant tumors, both in children and adults. The molecular events related to this resistant phenotype are far from being fully understood. For many pediatric tumors, molecular assays are starting to give insights about the complex relationship between tumor and individual. In an era of genomic-based hypotheses, the understanding of the molecular events is of critical importance to better treat oncological diseases. New techniques such as cDNA microarrays, real-time PCR, spectral karyotyping (SKY) and comparative genomic hybridization (CGH) represent new tools that may be useful in identifying genetic pathways or events beneath drug resistance. Researchers, physicians and pharmaceutical scientists are designing new pharmacological approaches and drugs for treating those resistant tumors based upon their molecular pattern of resistance. This may represent the ‘era of the disease in the search for its specific drug’ and not the opposite anymore. This special issue covers some very exciting aspects related to drug resistant phenotype in cancer. Dr. Styczynski presents a thorough review about drug resistance in childhood acute myeloid leukemia. Dr. Vidal et al. focus on drug resistance in myelodysplastic syndromes and describe an approach on the epigenetic process of methylation in that disease. Drs. Tu Anh Dang and Tsz-Kwong Man introduce the bioinformatic classification of sarcomas using genomic and proteomic profilings. Drs. S.W. Warmann and J. Fuchs gave us an excellent analysis on drug resistance in children with hepatoblastoma. Dr. Ramachandran reviews ways to inhibit the multidrug resistance mechanisms in renal tumors.Finally, Dr. Valera et al. examine drug-resistance in central nervous system tumors over the past decade, evolving from the traditional cell-resistance model to the genetically driven approaches on therapy. Specialists in the field discuss a number of molecular events in some difficult-to-treat neoplastic diseases, both in children and adults. I sincerely hope that this special issue will be of interest to researchers in their quest to find more rationale therapeutic approaches.