Symbiotic nitrogen fixation (SNF) in the interaction between the soil bacteria Sinorhizobium meliloti and legume plant Medicago sativa is carried out in specialized root organs called nodules. During nodule development, each symbiont must drastically alter their proteins, transcripts and metabolites in order to support nitrogen fixation. Moreover, bacteria within the nodules are under stress, including challenges by plant antimicrobial peptides, low pH, limited oxygen availability, and strongly reducing conditions, all of which challenge proteome integrity. S. meliloti stress adaptation, proteome remodeling and quality control are controlled in part by the large oligomeric protease complexes HslUV and ClpXP1. To improve understanding of the roles of S. meliloti HslUV and ClpXP1 in free-living conditions and in symbiosis with M. sativa, we generated ΔhslU, ΔhslV, ΔhslUV, and ΔclpP1 knockout mutants. Shoot dry weight of M. sativa plants inoculated with each deletion mutant was significantly reduced, suggesting a role in symbiosis. Further, slower free-living growth of ΔhslUV and ΔclpP1 suggest HslUV and ClpP1 were involved in adapting to heat stress, while ΔhslU and ΔclpP1 mutants were sensitive to kanamycin. All deletion mutants produced less exopolysaccharide and succinoglycan, as shown by replicate spot plating and Calcofluor binding. We also generated endogenous C-terminal eGFP fusions to HslU, HslV, ClpX and ClpP1 in S. meliloti. Using anti-eGFP antibodies, native coimmunoprecipitation experiments of proteins from free-living and nodule tissues were performed and analyzed by mass spectrometry. The results suggest HslUV and ClpXP were closely associated with ribosomal and proteome quality control proteins, and identified several novel putative protein-protein interactions.