In 1923, Dr. Harry M. Wegeforth of the newly opened San Diego Zoo asked Klauber to identify several species of snake recently acquired.

The result of that considerable amount of time and amassed data was his magnum opus, the two-volume book entitled Rattlesnakes: Their Habits, Life Histories and Influence on Mankind, published in 1956.

[11] In 1932, Klauber presented a paper on a triangular, non-spiral matrix to the Mathematical Association of America demonstrating geometric regularity in the distribution of the primes.

[13][14] Klauber's interest in mathematics—and the extensive samples of rattlesnakes that he accumulated for study—led to his most significant contribution to herpetology, the application of statistical methods to aid in the classification of reptiles.

He pioneered the use of quantitative analysis in herpetology to determine variation in snakes and to weigh the differences between species and subspecies.