Abstract: Provided herein are Complement Factor I (CFI) variants that exhibit at least one improved characteristic relative to a wild type CFI. CFI variants of the disclosure can exhibit tunable specificity and activity. Also included are CFI-containing fusion constructs comprising at least one domain of CFI, for example, wild type full length CFI fused to human serum albumin. Also included are methods of making and using such CFI variants and fusion constructs. The CFI variants and fusion constructs provided herein may be useful for treating a disease or condition associated with dysregulation of the complement system or a deficiency of CFI.