Musca domestica L., the common house fly, is a cosmopolitan carrier of human and livestock disease pathogens. The species exhibits resistance to many insecticides; therefore, effective M. domestica insecticide resistance management programs are required worldwide. In the present study, the development of alpha-cypermethrin resistance, realized heritability (h2), instability of resistance trait (DR), and cross-resistance (CR) was investigated in an alpha-cypermethrin-selected M. domestica strain (Alpha-Sel) across 24 generations (Gs). Compared with an alpha-cypermethrin-unselected strain (Alpha-Unsel), resistance to alpha-cypermethrin increased from 46.4-fold (G5) to 474.2-fold (G24) in Alpha-Sel females and 41.0-fold (G5) to 253.2-fold (G24) in Alpha-Sel males. Alpha-cypermethrin resistance declined by between –0.10 (G5) and –0.05 (G24) in both M. domestica sexes without insecticide exposure for 24 generations. The h2 of alpha-cypermethrin resistance was 0.17 and 0.18 for males and females, respectively, in G1–G24. With selection intensities of 10–90%, the G values required for a tenfold increase in the LC50 of alpha-cypermethrin were 6.3–53.7, 4.1–33.8, and 3.0–24.7, given h2 values of 0.17, 0.27, and 0.37, respectively, and a constant slope of 2.1 for males and h2 values of 0.18, 0.28, and 0.38, respectively, and a constant slope of 2.0 for females. Compared with Alpha-Unsel, Alpha-Sel M. domestica exhibited moderate CR to bifenthrin (15.5-fold), deltamethrin (28.4-fold), and cyfluthrin (16.8-fold), low CR to two pyrethroids and five organophosphates, and no CR to insect growth regulators. The instability of resistance trait, low h2, and absent or low CR associated with alpha-cypermethrin resistance in M. domestica indicate resistance could be managed with rotational use of the insecticide.