With a suite of sample preparation tools at one’s disposal, where does one start? Theory can certainly provide guidance, but practical considerations may a better north star for the clinical laboratory environment. Certain aspects, such as analytical measurement requirements based on defined clinical reference intervals, can be a quick adjudicator for the type of sample preparation needed (i.e. dilutive or concentration approach) but not prescribe the exact procedure. Other practical considerations within the laboratory can include; turnaround time, laboratory/personnel requirements, automation, environmental/health safety, and cost. If not taken into account, one can end up with a sample preparation protocol which is labor intensive and costly. Is that necessary? Can a method be more efficient from a cost and labor perspective and not sacrifice quality? Examples of such considerations and method development journey resulting in two possible sample prep protocols are compared and discussed herein. Goals are to arm one with pragmatic and practical considerations for method development of robust clinical methods along with design and interpretation of fundamental experiments required to provide confidence in sample prep methods.