The estrogen receptor-α (ER), progesterone receptor (PR) and androgen receptor (AR) are structurally related steroid hormone receptors that function as nuclear transcription factors by binding to DNA and interacting with a host of other nuclear proteins to regulate gene transcription. The pleiotropic actions of these receptors are determined in part by the “social network” of interacting proteins that are engaged. Recent advances in proteomic technologies has allowed unbiased investigation of the protein-protein interaction network (interactome) of a factor of interest. One of these is a technique called RIME (Rapid Immunoprecipitation and Mass spectrometry of Endogenous proteins). We have been utilising RIME to delineate in a dynamic, quantitative and non-biased way the proteins that interact with ERα, PR or AR under different experimental conditions associated with sex steroid receptor mediated growth of breast and prostate cancer. In this talk, I will describe the technique and its capabilities then present vignettes involving the identification of novel steroid receptor interacting proteins using RIME. How these newly identified steroid receptor interacting proteins influence receptor activity and the clinical implications will be also be addressed.