Nonsteroidal antiinflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation. Some undesirable effects are linked with NSAIDs such as the gastrointestinal tract (GIT) toxicity and cardiovascular disturbances. At present the preparation of a hybrid molecular technique is being used to produce new analgesic and antiinflammatory molecules. Attachment of NSAIDs with nitric oxide and hydrogen sulfide releasing molecules produced some gastroprotective agents with improved analgesic and antiinflammatory activities. Combination of NSAIDs with different biologically active 5-membered, 6-membered, and condensed heterocyclic rings has also led to the formation of some potent molecules. Some of these hybrid molecules, e.g., ibuprofen thiazole, exhibited less GIT toxicity, while others showed selectivity for COX-2 enzyme, e.g., quinazolinone pyrimidine and benzothiophene rhodanine hybrids. COX-2 selectivity was also exhibited by hybrids of NSAIDs with natural molecules such as salicylates resveratrol, chromone oxindole, and chrysin indole pyrazole. The preparation of new hybrid molecules is significant because they can serve as a lead compound for the discovery and development of safer analgesic and antiinflammatory agents.