We investigate the high-pT tails of the pp → ℓν and pp → ℓℓ Drell-Yan processes as probes of New Physics in semileptonic interactions with an arbitrary flavor structure. For this purpose, we provide a general decomposition of the 2 → 2 scattering amplitudes in terms of form-factors that we match to specific scenarios, such as the Standard Model Effective Field Theory (SMEFT), including all relevant operators up to dimension-8, as well as ultraviolet scenarios giving rise to tree-level exchange of new bosonic mediators with masses at the TeV scale. By using the latest LHC run-II data in the monolepton (eν, μν, τν) and dilepton (ee, μμ, ττ, eμ, eτ, μτ) production channels, we derive constraints on the SMEFT Wilson coefficients for semileptonic four-fermion and dipole operators with the most general flavor structure, as well as on all possible leptoquark models. For the SMEFT, we discuss the range of validity of the EFT description, the relevance of mathcal{O} (1/Λ2) and mathcal{O} (1/Λ4) truncations, the impact of d = 8 operators and the effects of different quark-flavor alignments. Finally, as a highlight, we extract for several New Physics scenarios the combined limits from high-pT processes, electroweak pole measurements and low-energy flavor data for the b → cτν transition, showing the complementarity between these different observables. Our results are compiled in HighPT (https://highpt.github.io), a package in Mathematica which provides a simple way for users to extract the Drell-Yan tails likelihoods for semileptonic effective operators and for leptoquark models.