Background: Human immunodeficiency virus 1 (HIV-1) infection is the primary cause of the acquired immunodeficiency syndrome (AIDS). Worldwide, approximately 37 million people are infected (UNAIDS, 2014), most of them in developing countries. A vaccine is not available and current treatment strategies and diagnostics are expensive and require appropriate medical infrastructure. As a lentivirus of the family Retroviridae, HIV-1 reverse transcribes its RNA into double stranded DNA that integrates into the host genome during infection, establishing a stably integrated provirus that serves as a template for the production of progeny virus. The earliest steps during infection are critical for onset of disease, progression and clinical outcome. Methods: Here we review the current literature of known interactions between host cell factors and HIV-1 in the early infection steps and discuss them as possible targets for new treatment strategies. Results: Targeting the earliest interactions of the virus with host cell factors is an attractive way to prevent provirus formation, underlined by the evolution of multiple antiviral host cell barriers at this stage. HIV-1 has to overcome these restrictions by either counteracting them directly or by escape mutations. At the same time, viral fitness requires preservation of viral structures that interact with host components, thereby avoiding recognition of viral nucleic acids, like reverse transcription intermediates, by innate pattern recognition receptors. Conclusion: Future drug development, improvement of existing drugs acting in the earliest stages of the HIV-1 replication cycle as well as specifically targeting interactions of viral components with host cell factors required for HIV-1 infection will likely advance current therapy strategies.