The South American tomato pinworm, Tuta absoluta (Meyrick, 1917) (Lepidoptera: Gelechiidae), is heavily targeted by insecticide applications. Methoxyfenozide is highly effective against T. absoluta with reduced side effects to natural enemies. This work aimed to (1) genetically and biochemically characterize resistance of the T. absoluta GBN population to methoxyfenozide, (2) establish cross resistance profiles with other insecticide groups and (3) monitor resistance in populations with the goal of improving T. absoluta insecticide resistance management (IRM). Methoxyfenozide resistance was completely recessive, polyfactorial and autosomal. Effective dominance revealed that 10 mg methoxyfenozide/L would be enough to eliminate susceptible homozygotes and heterozygotes, thus used to diagnose resistance in field populations. The synergism of methoxyfenozide toxicity in the resistant population for PBO (SR = 95×), DEF (SR = 51×) and DEM (SR = 45×), suggested monooxygenases, esterases and glutathione S-transferases as resistance mechanisms. However, only monooxygenase activity appeared to be involved in methoxyfenozide resistance. Resistance ratio for methoxyfenozide (2352-fold) after selection and cross-resistance ratios of a lab-selected GBN strain (“GBN-Sel”) were significant relative to a susceptible strain “JDR1-Sus” for tebufenozide (656-fold), cartap hydrochloride (10.68-fold), deltamethrin (4.70-fold), abamectin (2.65-fold), lufenuron (2.22-fold) and indoxacarb (1.92-fold), with negative cross-resistance to spinetoram (0.32-fold). Evidence of control failures was observed in 10 field populations of T. absoluta (mortalities between 13 and 76%), and all populations showed frequencies of resistant phenotypes (percentage survivorship ranging between 4 and 96%). A rational basis for managing resistance to bisacylhydrazines is discussed, along with details of recommended T. absoluta resistance management tactics.