The tripartite motif (TRIM)-containing proteins are involved in many cellular functions such as cell signaling, apoptosis, cell differentiation, and immune modulation. TRIM5 proteins, including TRIM5α and TRIM-Cyp, are known to possess antiretroviral activity against many different retroviruses. Besides being retroviral restriction factors, TRIM5 proteins participate in other cellular functions that have recently emerged in the study of TRIM5α. In this review, we discuss properties of TRIM5α such as cytoplasmic body formation, protein turnover, and trafficking. Also, we discuss recent insights into innate immune modulation mediated by TRIM5α, highlighting the various functions TRIM5α has in cellular processes.