Leukemias and lymphomas are relatively common, affect all ages and demonstrate extra-ordinary biologic, morphologic and clinical heterogenecity. Immunotherapy, mainly antibody-based therapy in non-Hodgkin’s lymphomas, has become one of the success stories of targeted therapy today especially rituximab which is in broad clinical use all over the world. The combination with chemotherapy increases remission rates and remission duration. The primary advantage of using T cells for adoptive therapy is their ability to specifically target tumor cells through the recognition of differentially expressed tumor proteins presented on the cell surface. The story of imatinib, a tyrosine kinase inhibitor, is one of the first examples of a successful targeted therapy in hematological malignancies. The development of second and third generations of tyrosine kinase inhibitors was necessary in resistant cases. A number of receptor tyrosine kinase inhibitors are being used in hematologic malignancies to block angiogenesis through vascular endothelial growth factor (VEGF) inhibition. Emerging knowledge about molecular mechanism of apoptosis dysregulation in leukemia has revealed a plethora of potential drug discovery targets as well as for inhibitors of DNA methylation. Initial treatment with azacitidine or decitabine, followed by histone deacetylases inhibitors, can produce additive or synergistic effects for re-expression of transcriptionally silenced genes having clinical benefit in patients with AML and MDS.