β-Cell replacement by means of whole pancreas or isolated islet transplantation are established approaches to the treatment of diabetes caused by severe β-cell deficiency, most often established type 1 diabetes with undetectable or very low levels of C-peptide. The primary goal for β-cell replacement is to provide on-target glycemic control in the absence of severe hypoglycemia events, which is generally associated with a clinically significant reduction or elimination of insulin requirements attributed to restoration of endogenous insulin secretion (measured by C-peptide) from the β-cell graft. Validation of glycemic control metrics derived from continuous glucose monitoring (CGM) allows for simultaneous assessment of average glycemia, glucose variability/glycemic lability, time-in-range for on-target glycemic control, and time-below-range for exposure to hypoglycemia, including clinically important, serious hypoglycemia. These CGM-based metrics should be used to both compare outcomes with various forms of β-cell replacement, and to compare cell-based therapies to approaches based on artificial pancreas technologies.