Acute lymphoblastic leukaemia (ALL) is the most common paediatric malignancy. Despite the fact that the outcome of treatment of ALL in children has improved in the last decades, still as many as 20% of children will undergo treatment failure. Over the last years, there have been great efforts to characterize the genetic alterations of leukaemic cells, which could affect the clinical course of the disease and become new markers that may be targeted with novel therapies. Genomic profiling and sequencing studies have not only identified new subtypes of ALL (e.g. Philadelphia chromosome-like ALL, early T-cell precursor ALL) but also helped to understand the genetic basis of leukaemogenesis and predict treatment failure. Those efforts contributed not only to better risk stratification of children with ALL, but also to development of new tailored therapeutic strategies. So far, improvements in survival of children with Ph⁺ ALL (Philadelphia positive ALL) have been demonstrated due to combination of intensive chemotherapy with tyrosine kinase (TK) inhibitor (imatinib). There are also some pre- and clinical testing of other inhibitors (TK, FLT3, PI3K/mTOR, MEK) and specific antibodies (CD19 and CD22). Widespread use of modern diagnostic techniques at the early stage of the disease would enable rapid identification of children with a high-risk leukaemia and use of more intensive and tailored therapy.