The sodium-glucose-cotransporter-2 (SGLT-2) is a high-capacity glucose transport protein on the renal tubule cell surface that reabsorbs glucose excreted in the urine. The medication class of SGLT-2 inhibitors including the US Food and Drug Administration (FDA) approved empagliflozin (Jardiance, Boehringer Ingelheim and Eli Lilly), dapagliflozin (Farxiga, AstraZeneca and Bistrol-Myers Squibb Company), canagliflozin (Invokana, Janssen Pharmaceuticals), bexagliflozin (Brenzavvy, TheracosBio), and ertugliflozin (Steglatro, Merck & Company and Pfizer) work by inhibiting glucose reabsorption in the renal tubule, thus enhancing urinary glucose excretion and diuresis. Other effects of these drugs on the cardiovascular and renal systems are described, though many mechanisms are not yet fully elucidated. Although these drugs were designed for glycemic control for the treatment of type 2 diabetes (T2D), the early FDA-mandated cardiovascular evaluation uncovered their significant impact on major adverse cardiovascular events and renal dysfunction. In the last 10 years, there has been increased interest and adoption in the use of SGLT-2 inhibitors to target renal and cardiovascular disease (CVD) outcomes irrespective of diabetes status. Major clinical benefits of SGLT-2 inhibitors include improvements in A1c with minimum hypoglycemia, weight, heart failure (HF) hospitalization, renal dysfunction including albuminuria and time to dialysis, systolic blood pressure, and cholesterol. Given this broad impact, there are growing data evaluating the benefits of initiating SGLT-2 inhibitors and now continuing them from ambulatory to inpatient settings. Data and rationale behind their inpatient use and appropriate precautions are summarized below.