Heme is an essential cofactor that plays a key role in diverse biological processes. Free heme, however, is hydrophobic and toxic to cellular macromolecules. C. elegans lack the heme biosynthetic pathway, and therefore contains a highly regulated trafficking network to redistribute heme throughout the worm. A forward genetic screen in C. elegans identified thirteen mutants which grow at toxic concentrations of heme in axenic liquid media. These mutants, termed them for Toxic HEMe resistant, belong to five complementation groups of which IQ7280, IQ7310, IQ8280 and IQ9110 strains were characterized. them mutants exhibit abnormal responses to heme analogs, mating defects, and growth on heme-deficient bacteria. Pyrosequencing analysis mapped IQ7310, IQ8280, and IQ7280 to a common genetic interval on chromosome I and IQ9110 to chromosome V. Solexa deep sequencing identified mutations in novel genes which may play an essential role in organismal heme homeostasis.