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Tenofovir is a nucleotide analog inhibitor used in monotherapy as the first-line treatment for chronic hepatitis B virus (HBV) infection. This drug requires a two-step phosphorylation using cellular kinases. The active triphosphate form inhibits viral DNA polymerase. Tenofovir has a very low oral bioavailability following oral administration. As such, its oral administration requires the use of prodrugs: either tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). TAF has demonstrated a lower kidney and bone toxicity than TDF. TAF and TDF treatments enable prevention of chronic hepatitis B complications—cirrhosis and hepatocellular carcinoma. Prevention of these complications requires a virological response to the treatment, defined as undetectable HBV DNA. TDF and TAF have virological response rates ranging from 64 to 94% after one year of treatment. This rate depends on the HBV viral load at diagnosis, HBe antigen status, mutations in the HBV polymerase gene (Pol/RT), and patient compliance to the treatment. Tenofovir has a high genetic barrier and resistance mutations to this drug have not yet been described. However, mutations rt181T/V and/or rtN236T have been associated with reduced susceptibility to TDF/TAF in vitro and delayed response in vivo. The recently described mutations CYEI and rtA194T have been associated with reduced susceptibility to TDF/TAF in vitro without any change in viral response in vivo. Patient compliance can be improved using cognitive behavioral therapy, supporter interventions, and a text messaging service. Finally, some genetic polymorphisms in MRP2 (multidrug resistance-associated protein 2) and MRP4 (multidrug resistance-associated protein 4) efflux transporters could be associated with TDF toxicity and virological response to TDF or TAF. In terms of a functional HBV cure, TDF and TAF are likely to be still used, alongside new antivirals. For this reason, it is important to further characterize the pharmacological and virological factors associated with a partial virological response to tenofovir.