Abstract: Provided herein are genetically engineered Pichinde viruses that include three ambiense genomic segments. The first genomic segment includes two coding regions encoding a Z protein and a L RdRp protein. The second genomic segment includes a coding region encoding a nucleoprotein (NP) and the third genomic segment includes a coding region encoding a glycoprotein. Each of the second and third genomic segments include an additional coding region that may encode a reovirus sigma C protein or a reovims sigma B protein. In one embodiment, a genetically engineered Pichinde virus encodes a reovims sigma C protein and a reovirus sigma B protein. Also provided herein is a reverse genetics system for making genetically engineered Pichinde virus, and a collection of vectors that can be used to produce genetically engineered Pichinde virus. Further provided are methods for using a reverse genetics system, and methods for treating a reovirus infection in a subject.