Non-steroidal anti-inflammatory drugs (NSAIDs) comprise the group of structurally diverse but similarly acting compounds that are used for relieving signs and symptoms of inflammation, especially in treatment of rheumatic diseases. Recent reports suggested potential association between regular use of NSAIDs and the risk of development of hematological malignancies. However, the data distinctly differ depending on type of NSAID used, period of its administration and type of malignancy. Regular use of aspirin and other NSAIDs was shown to correlate with reduced risk of lymphoid malignancies. Frequent use of aspirin was found to be associated with decreased risk of acute leukemia (AL) development. In contrast, correlation between long-term acetaminophen usage and increased incidence of AL and multiple myeloma (MM) was indicated. On the other hand, NSAIDs were found to exert anti-cancer effects, inhibiting proliferation and invasive growth or inducing cell apoptosis in several tumors, including hematologic malignancies. One of those agents, non-cyclooxygenase 2-inhibiting R-enantiomer of etodolac (SDX-101), exerts cytotoxic effects against chronic lymphocytic leukemia (CLL) and MM cells, and is currently investigated in phase II clinical trial in CLL. The indole-pyran analogue of SDX-101, SDX-308 (CEP-18082), showed more potent cytotoxicity than SDX-101 against MM cells and inhibited osteoclast formation and activity of mature osteoclasts. Thus, SDX-308 may be an ideal agent for bone disease in MM and related diseases. Another analogue of SDX-101, SDX-309, showed also significant anti-tumor activity in first preclinical studies. The potential role of NSAIDs in prevention and treatment of hematologic malignancies is the subject of this review.