Ribosomes are made up of parts that interact so strongly that a mutation in one of them can mask the effect of mutation in another. For example, when a mutation to neomycin resistance, which is a ribosome mutation, is introduced into cells carrying a ribosome mutation to spectinomycin resistance, some of the doubly mutant strains were phenotypically sensitive to spectinomycin, even though the mutation to spectinomycin resistance is still intact and recoverable in appropriate crosses. The neomycin mutant alleles that cause masking were shown by genetic tests to be in an identified locus that affects ribosomes. Protein synthesis in cell-free extracts of a double mutant strain was as sensitive to the action of spectinomycin as was the extract of the doubly sensitive parental strain. Thus, the masking effect of neomycin mutations on the spectinomycin mutation is exerted at the level of the ribosomes.We conclude that the genetic analysis of an organelle like the ribosome is likely to be severely complicated by pleiotropic effects and by interactions among its component parts and that the ribosomal binding sites for spectinomycin and neomycin are partially interdependent. These results suggest that the function of the ribosome requires a very precise conformation of all its elements, some of which are interdependent. Modification in one element can thus alter the function of another or even render the entire structure nonfunctional.