The melon aphid, Aphis gossypii Glover (Hemiptera: Aphididae), is a highly polyphagous sap sucking pest on wide varieties of crops including cotton and vegetables. It is a notorious vector of many plant viruses that are persistently and non-persistently transmitted. In nature, aphids are regulated by their natural enemies. However, chemical control remains a major management tool even though resistance to insecticides has been documented worldwide. A better understanding of mechanisms by which insecticide resistance occurs and its early detection is desirable to develop effective management strategies. The present investigation was conducted to study the development of resistance to an organophosphate (OP) compound-dimethoate, identify biochemical mechanism(s) involved in resistance and study cross-resistance to imidacloprid in laboratory selected A. gossypii strains in comparison to susceptible strains. Bioassay studies revealed that the LC50 values increased dramatically with dimethoate selection in resistant strains and the resistance ratio (RR) was 270-, 243-and 210-fold greater than that of the susceptible strains by 30 th generation. Further, biochemical assays revealed enhanced activities of carboxylesterases (CarE), glutathione S-transferases (GSTs) and cytochrome P450-mediated p-Nitroanisole O-demethylase (PNOD) in resistant strains supporting their role in dimethoate detoxification. This study thus revealed that enhanced activity of detoxifying enzymes viz., CarE, GSTs and PNODs is one of the mechanisms underlying dimethoate resistance in A. gossypii collected from South India. Interestingly, the possibility of negatively correlated cross-resistance to imidacloprid was identified in three OPresistant strains exhibiting 2.97-, 2.56-and 3.76-fold sensitivity to imidacloprid (a novel neonicotinoid). This indicated that the latter was less affected by the resistance mechanism(s) present.