The ruffled border membrane is a giant lysosome-related secretory organelle unique to bone-digesting osteoclasts. The fusion of secretory lysosomes with the ruffled border equips it with sets of lysosomal membrane proteins that are requisite for the cell’s bone resorptive function. Despite its crucial importance, we still lack elementary information on the protein composition of the ruffled border membrane, including the numbers and identities of lysosomal membrane residents whose usual functions are to facilitate the exchange of molecules across its membrane (i.e. transporters). To extend the molecular inventory of membrane transport proteins operating at the ruffled border, we have combined biochemical methods with bottom-up proteomics. Through an in-gel tryptic digestion, and nanoflow liquid chromatography high-resolution tandem mass spectrometry (LC-MS/MS) we have unbiasedly surveyed the ruffled border lysosomal membrane proteome using isolated secretory lysosomes as a surrogate organelle. Our analysis identified 3804 master proteins (two or more unique peptides) of which 1100 are functionally assigned as membrane transport proteins. These transport proteins included established components of the osteoclasts’ ‘bone-resorbing machinery’ including the entire V-ATPase proton pump complex and chloride ion channels thus validating our approach. It also uncovered several other membrane transport proteins predicted to reside on lysosomes but whose functions remain to be assigned, including several members of the secondary active transporter superfamily of solute carriers (Slc). By combining a suite of biochemical, cell biology and genetic studies, we demonstrated the robustness and utility of our proteomic screen using the Slc37a2 transporter as a prototype. This approach has allowed us, for the first time, to unmask the osteoclast lysosomal transport protein cache (termed the ‘Transportome’), that will serve as a powerful resource for the future interrogation of ‘orphan’ lysosomal transport proteins operating at the osteoclast ruffled border and may account for a subset of human bone-sclerosing disorders for which the underlying molecular determinant remains unknown.