In this work, an expedient approach to the preparation of cis-1,2disubstituted (fluoro)alkyl cyclobutanes is developed. The proposed synthetic methodologies are based on simple transformations of commercially available starting materials, enabling access to a variety of valuable (fluoro)alkyl-substituted cyclobutane building blocks (amines, carboxylic acids, and alcohols). In particular, reductive dehalogenation strategy granted access to cis-(and trans-) CH3-substituted building blocks in 3 to 6 steps with preparative yields on up to 39 g scale. CH2F-substituted cyclobutanes were accessed via the nucleophilic substitution in the corresponding activated bis(hydroxymethyl) derivatives; further functional group transformations produced target building blocks in reasonable yields on up to 5 g scale. Other fluorinated substituents (i.e., CHF2, CF3, and C2F5) were introduced through addition of the corresponding fluorine-containing reagents (PhSO2CHF2, TMSCF3, or TMSC2F5) to the carbonyl group in a properly 2functionalized cyclobutanone; the subsequent 6-step synthetic scheme (including deprotection, alcohol oxidation, elimination of the activated alcohol species, and cis-selective catalytic hydrogenation) gave the desired cis-fluroalkyl-substituted cyclobutane building blocks. Physicochemical characterization of the prepared compounds revealed a crucial role of the relative configuration of the substituents, especially in the case of CF3 and C2F5 groups. The pKa values in the discussed series of cis-and trans-substituted cyclobutanes varied in an expected manner (with more fluorine atoms typically leading to increased acidity). For most derivatives studied, the LogP values followed the trends established in the previous works and increased in the series: CH2F≤CHF2<CH3≤CF3<C2F5. Nevertheless, the lipophilicity of cis-isomeric CF3-and C2F5-substituted model amides was lower than might be anticipated. Analysis of the molecular electrostatic potential surfaces (MEPS) of the discussed compounds revealed increased polarization of the α-C-H bond, which could be a possible reason of the observed decrease in the lipophilicity. Conformational analysis (either by computational studies or using X-ray diffraction and NMR experimental data) revealed the prevalent synclinal orientation of the C-F and α-C-H bond in the case of CH2F-and CHF2-substituted derivatives. On the contrary, antiperiplanar orientation of one of the C-F and α-C-H bonds for the cis-isomeric CF3-and C2F5-substituted cyclobutanes enabled H-H/C-F hyperconjugation, possibly being the reason behind the observed positive polarisation of the molecular surface and hence lowered lipophilicity.