A histologic diagnosis of amyloidosis requires acquiring tissue containing amyloid fibrils from an affected organ or alternate site. The biopsy site and staining techniques may influence testing accuracy. We present a case in which systemic amyloidosis was suspected; however, biopsies of the bone marrow, an osteosclerotic bone lesion, arterial and venous vessels, and the fat pad were all negative for the diagnostic Congo red stain. An eventual renal biopsy demonstrated AL-amyloidosis, kappa light chain associated with extensive vascular interstitial, and glomerular, involvement. Choice of biopsy site, as well as staining and analysis of the tissue, can influence sensitivity and specificity of amyloid testing. Fat-pad biopsies are less invasive and offer reasonable sensitivity. Bone marrow samples are only diagnostic up to 63% of the time. A renal biopsy offers improved sensitivity and is generally safe in experienced hands, but is a more invasive procedure with increased number of relative contraindications and complications. The choice of the biopsy site should be based on considering the expected yield, accessibility of the site, and the risks associated with the procedure.