More than 50 years have passed since Dr. Stewart Adams discovered ibuprofen as post-aspirin non-steroidal anti-inflammatory drug (NSAID) effective primary against rheumatoid arthritis triad (anti-inflammatory, analgesic and antipyretic). Later, new indications were revealed for ibuprofen, including prevention of thrombosis, treatment of patent ductus arteriosus in preterm and/or low birth weight infants, prevention of Parkinson's disease, migraine, colon cancer, cardiovascular and neurodegenerative diseases. Ibuprofen was invented via rational design rather than molecular modeling and like aspirin it is non-selective inhibitor of both isoforms of cyclooxygenase (COX) that produce pro-inflammatory prostaglandins. Unlike selective COX-2 inhibitors, ibuprofen is a multifunctional drug, the non-COX targets of which encompass various effects, e.g. inhibition of leukotriene production and leukocyte functions, inhibition of production of cytokines, some transcription factors, MAPkinase, nuclear receptors, heat shock proteins, increasing anandamide production via inhibition of its hydrolase, etc. Beside their potent anti-inflammatory activities, NSAIDs are associated with significant adverse effects on gastrointestinal tract and kidneys, which pose critical limits to their clinical use in chronic conditions. In order to diminish ibuprofen side effects and make it safer to patient, a new generation of ibuprofen drugs was developed. There are two main ways for their design: a) construction of various drug formulations with increased bioavailability or ibuprofen derivatives with almost inert pro-drug moiety and b) development of hybrid multifunctional drugs, where both molecular parts are pharmacologically active. The last way led to the invention of nitric oxide- and hydrogen sulfide-releasing NSAIDs, ibuprofen advanced by complexing with polymers, or conjugated with amino acids, peptides, heterocyclic compounds, and nucleotides. The review will cover briefly known mechanisms of ibuprofen activities with the focus on the hybrid ibuprofen drugs, their design and pharmacology. © 2013 by Nova Science Publishers, Inc. All rights reserved.