Bacillus sphaericus Neide, recently renamed as Lysinibacillus sphaericus Meyer and Neide, is a spore-forming bacterium that possesses various levels of larvicidal activity, depending on the strains, against some mosquito species. Products based on most active strains such as 2362, 2297, 1593, C3-41 that bear binary toxins, as well as mosquitocidal toxins at various levels, have been developed to combat mosquito larvae worldwide. Resistance in wild Culex mosquito populations has been reported since 1994 from France, Brazil, India, China, Thailand, and Tunisia. Laboratory studies to evaluate resistance development risk have been conducted by many groups of scientists worldwide. Products based on L. sphaericus strain 2362 were registered in the United States in 1990s, and their use for mosquito control has been increased considerably since invasion of West Nile virus. This report documents the first occurrence of high-level resistance to L. sphaericus in a natural population of Culex pipiens L. in Chico, CA, where resistance ratio was 537.0 at LC50 and 9,048.5 at LC90 when compared with susceptible laboratory colony of the same species. Susceptibility profile to other groups of pesticides with different modes of action was also determined. Various levels of resistance or tolerance were noticed to abamectin, pyriproxyfen, permethrin, and indoxacarb. Resistance management and susceptibility monitoring strategies are discussed and recommended.