Erythroid-specific Krüppel-like factor 1, or KLF1, is an integral transcriptional activator for erythropoiesis. Genetic variants within KLF1 can result in a range of erythropoietic clinical phenotypes from benign to significant. The In(Lu) phenotype refers to changes in the quantitative expression of blood group-associated red cell surface molecules due to KLF1 variants which are otherwise clinically benign. These clinically benign KLF1 variants are associated with a reduced expression of 1 or more red cell membrane proteins/carbohydrates that carry blood group antigens for the LU (Lutheran), IN (Indian), P1PK, LW (Landsteiner-Wiener), KN (Knops), OK, RAPH, and I blood group systems. This is of significance during routine serologic blood typing when expression falls below the test sensitivity and therefore impacts on the ability to accurately detect the presence of affected blood group antigens. This is of clinical importance because the transfusion requirements for individuals with the In(Lu) phenotype differ from those of individuals that have a true Lunull phenotype. With this review, we summarize the current body of knowledge with regard to the In(Lu) phenotype and associated KLF1 variants. Our review also highlights discordant reports and provides insights for future research and management strategies. Serological heterogeneity in blood group expression of In(Lu) individuals has been shown, but studies are limited by the low prevalence of the phenotype and therefore the small numbers of samples. They are further limited by availability and inconsistent application of serological reagents and varying test algorithms. With the advent of genome sequence-based testing, an increasing list of In(Lu)-associated KLF1 variants is being revealed. The spectrum of effects on blood group expression due to these variants warrants further attention, and a consistent methodological approach of studies in larger cohorts is required. We propose that a recently reported testing framework of standardized serological studies, flow cytometry, and variant analysis be adopted; and that the international databases be curated to document KLF1 variability and the resultant In(Lu) red cell blood group expression. This will provide better classification of KLF1 variants affecting blood group expression and allow for phenotype prediction from genotype, accurate typing of In(Lu) individuals, and better transfusion management of related challenging transfusion scenarios.